Benzo-fused lactams promote release of growth hormone

ABSTRACT

There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. Growth promoting compositions containing such benzo-fused lactams as the active ingredient therefore are also disclosed.

This application is a national stage application under 35 U.S.C. § 371of PCT/US/93/07791, filed Aug. 18, 1993, which is a continuation-in-partof application Ser. No. 07/936,975, filed Aug. 28, 1992, now U.S. Pat.No. 5,283,241.

BACKGROUND OF THE INVENTION

Growth hormone, which is secreted from the pituitary, stimulates growthof all tissues of the body that are capable of growing. In addition,growth hormone is known to have the following basic effects on themetabolic process of the body:

1. Increased rate of protein synthesis in all cells of the body;

2. Decreased rate of carbohydrate utilization in cells of the body;

3. Increased mobilization of free fatty acids and use of fatty acids forenergy.

A deficiency in growth hormone secretion can result in various medicaldisorders, such as dwarfism.

Various ways are known to release growth hormone. For example, chemicalssuch as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon,vasopressin, and insulin induced hypoglycemia, as well as activitiessuch as sleep and exercise, indirectly cause growth hormone to bereleased from the pituitary by acting in some fashion on thehypothalamus perhaps either to decrease somatostatin secretion or toincrease the secretion of the known secretagogue growth hormonereleasing factor (GRF) or an unknown endogenous growth hormone-releasinghormone or all of these.

In cases where increased levels of growth hormone were desired, theproblem was generally solved by providing exogenous growth hormone or byadministering an agent which stimulated growth hormone production and/orrelease. In either case the peptidyl nature of the compound necessitatedthat it be administered by injection. Initially the source of growthhormone was the extraction of the pituitary glands of cadavers. Thisresulted in a very expensive product and carried with it the risk that adisease associated with the source of the pituitary gland could betransmitted to the recipient of the growth hormone. Recently,recombinant growth hormone has become available which, while no longercarrying any risk of disease transmission, is still a very expensiveproduct which must be given by injection or by a nasal spray.

Other compounds have been developed which stimulate the release ofendogenous growth hormone such as analogous peptidyl compounds relatedto GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, whileconsiderably smaller than growth hormones are still susceptible tovarious proteases. As with most peptides, their potential for oralbioavailability is low. The instant compounds are non-peptidyl agentsfor promoting the release of growth hormone which may be administeredparenterally, nasally or by the oral route.

SUMMARY OF THE INVENTION

The instant invention covers certain benzo-fused lactam compounds whichhave the ability to stimulate the release of natural or endogenousgrowth hormone. The compounds thus have the ability to be used to treatconditions which require the stimulation of growth hormone production orsecretion such as in humans with a deficiency of natural growth hormoneor in animals used for food production where the stimulation of growthhormone will result in a larger, more productive animal. Thus, it is anobject of the instant invention to describe the benzo-fused lactamcompounds. It is a further object of this invention to describeprocedures for the preparation of such compounds. A still further objectis to describe the use of such compounds to increase the secretion ofgrowth hormone in humans and animals. A still further object of thisinvention is to describe compositions containing the benzo-fused lactamcompounds for the use of treating humans and animals so as to increasethe level of growth hormone secretions. Further objects will becomeapparent from a reading of the following description.

DESCRIPTION OF THE INVENTION

The novel benzo-fused lactams of the instant invention are bestdescribed in the following structural formula I: ##STR1## where L is##STR2## n is 0 or 1; p is 0 to 3;

q is 0 to 4;

w is 0 or 1;

X is C═O, O, S(O)_(m), ##STR3## m is 0 to 2; R¹, R², R^(1a), R^(2a),R^(1b) and R^(2b) are independently hydrogen, halogen, C₁ -C₇ alkyl, C₁-C₃ perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, --S(O)_(m) R^(7a), cyano,nitro, R^(7b) O(CH₂)_(v) --, R^(7b) COO(CH₂)_(v) --, R^(7b)OCO(CH₂)_(v), R⁴ R⁵ N(CH₂)_(v) --, R^(7b) CON(R⁴)(CH₂)_(v) --, R⁴ R⁵NCO(CH₂)_(v) --, phenyl or substituted phenyl where the substituents arefrom 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, or hydroxy;

R^(7a) and R^(7b) are independently hydrogen, C₁ -C₃ perfluoroalkyl, C₁-C₆ alkyl, substituted C₁ -C₆ alkyl, where the substituents are phenylor substituted phenyl; phenyl or substituted phenyl where the phenylsubstituents are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, orhydroxy and v is 0 to 3;

R^(3a) and R^(3b) are independently hydrogen, R⁹, C₁ -C₆ alkylsubstituted with R⁹, phenyl substituted with R⁹, or phenoxy substitutedwith R⁹ with the proviso that either R^(3a) or R^(3b) must be asubstituent other than hydrogen;

R⁹ is

R^(4b) R^(12b) NCON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12b) NCSN(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))CSN(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))CON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))COO(CH₂)_(v) --, R^(4b) R^(12b) NCOO(CH₂)_(v)--,

or R¹³ OCON(R^(12a))(CH₂)_(v) --, where v is 0 to 3.

R^(12a), R^(12b) and R^(12c) are independently R^(5a), OR^(5a), orCOR^(5a). R^(12a) and R^(12b), or R^(12b) and R^(12c), or R^(12a) andR^(12c), or R^(12b) and R^(4b), or R^(12c) and R^(4b), or R¹³ andR^(12a) can be taken together to form --(CH₂)_(r) --B--(CH₂)_(s) --where B is CHR¹, O, S(O)_(m) or NR¹⁰, m is 0, 1 or 2, r and s areindependently 0 to 3 and R¹ and R¹⁰ are as defined.

R¹³ is

C₁ -C₃ perfluoroalkyl, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, where thesubstitutents are hydroxy, NR¹⁰ R¹¹, carboxy, phenyl or substitutedphenyl; phenyl or substituted phenyl where the substituents on thephenyl are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy orhydroxy.

and v is as defined above;

R⁴, R^(4b), R⁵ and R^(5a) are independently hydrogen, phenyl,substituted phenyl, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl, C₃ -C₁₀alkenyl, substituted C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkynyl, or substituted C₃-C₁₀ alkynyl where the substituents on the phenyl, alkyl, alkenyl oralkynyl are from 1 to 5 of hydroxy, C₁ -C₆ alkoxy, C₃ -C₇ cycloalkyl,fluoro, R¹, R² independently disubstituted phenyl C₁ -C₃ alkoxy, R¹, R²independently disubstituted phenyl, C₁ -C₂₀ -alkanoyloxy, C₁ -C₅alkoxycarbonyl, carboxy, formyl or --NR¹⁰ R¹¹ where R¹⁰ and R¹¹ areindependently hydrogen, C₁ -C₆ alkyl, phenyl, phenyl C₁ -C₆ alkyl, C₁-C₅ -alkoxycarbonyl or C₁ -C₅ -alkanoyl-C₁ -C₆ alkyl; or R⁴ and R⁵ canbe taken together to form --(CH₂)_(r) --B--(CH₂)_(s) -- where B is CHR¹,O, S(O)_(m) or N--R¹⁰, r and s are independently 1 to 3 and R¹ and R¹⁰are as defined above;

R⁶ is hydrogen, C₁ -C₁₀ alkyl, phenyl or phenyl C₁ -C₁₀ alkyl;

A is ##STR4## where x and y are independently 0-3; R⁸ and R^(8a) areindependently hydrogen, C₁ -C₁₀ alkyl, trifluoromethyl, phenyl,substituted C₁ -C₁₀ alkyl where the substituents are from 1 to 3 ofimidazolyl, indolyl, hydroxy, fluoro, S(O)_(m) R^(7a), C₁ -C₆ alkoxy, C₃-C₇ cycloalkyl, R¹, R² independently disubstituted phenyl C₁ -C₃ alkoxy,R¹, R² independently disubstituted phenyl, C₁ -C₅ -alkanoyloxy, C₁ -C₅alkoxycarbonyl, carboxy, formyl, or --NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are asdefined above; or R⁸ and R^(8a) can be taken together to form--(CH₂)_(t) -- where t is 2 to 6; and R⁸ and R^(8a) can independently bejoined to one or both of R⁴ and R⁵ to form alkylene bridges between theterminal nitrogen and the alkyl portion of the A group wherein thebridge contains from 1 to 5 carbon atoms; and pharmaceuticallyacceptable salts thereof.

In the above structural formula and throughout the instantspecification, the following terms have the indicated meanings:

The alkyl groups specified above are intended to include those alkylgroups of the designated length in either a straight or branchedconfiguration. Exemplary of such alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl,isohexyl, and the like.

The alkoxy groups specified above are intended to include those alkoxygroups of the designated length in either a straight or branchedconfiguration. Exemplary of such alkoxy groups are methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy,isopentoxy, hexoxy, isohexoxy and the like.

The term "halogen" is intended to include the halogen atom fluorine,chlorine, bromine and iodine.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other.

Preferred compounds of the instant invention are realized when in theabove structural formula:

n is 0 or 1;

p is 0 to 3;

q is 0 to 2;

w is 0 or 1;

X is O, S(O)_(m), ##STR5## m is 0 to 2; R¹, R², R^(1a), R^(2a), R^(1b)and R^(2b) are independently hydrogen, halogen, C₁ -C₇ alkyl, C₁ -C₃perfluoroalkyl, --S(O)_(m) R^(7a), R^(7b) O(CH₂)_(v) --, R^(7b)COO(CH₂)_(v) --, R^(7b) OCO(CH₂)_(v) --, phenyl or substituted phenylwhere the substituents are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆alkoxy or hydroxy;

R^(7a) and R^(7b) are independently hydrogen, C₁ -C₃ perfluoroalkyl, C₁-C₆ alkyl, substituted C₁ -C₆ alkyl, where the substituents are phenyl;phenyl and v is 0 to 2;

R^(3a) and R^(3b) are independently hydrogen, R⁹, C₁ -C₆ alkylsubstituted with R⁹, phenyl substituted with R⁹, or phenoxy substitutedwith R⁹ with the proviso that either R^(3a) or R^(3b) must be asubstituent other than hydrogen;

R⁹ is

R^(4b) R^(12b) NCON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12b) NCSN(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))CON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))COO(CH₂)_(v) --,

R^(4b) R^(12b) NCOO(CH₂)_(v) -- or R¹³ OCON(R^(12a))(CH₂)_(v) --,

where v is 0 to 3.

R^(12a), R^(12b) and R^(12c) are independently R^(5a), OR^(5a), orCOR^(5a). R^(12a) and R^(12b), or R^(12b) and R^(12c), or R^(12a) andR^(12c), or R^(12b) and R^(4b), or R^(12c) and R^(4b), or R¹³ andR^(12a) can be taken together to form --(CH₂)_(r) --B--(CH₂)_(s) --where B is CHR¹, O, S(O)_(m) or NR¹⁰, m is 0, 1 or 2, r and s areindependently 0 to 3, R¹ is as defined above and R¹⁰ is hydrogen, C₁ -C₆alkyl, phenyl C₁ -C₆ alkyl or C₁ -C₅ alkanoyl-C₁ -C₆ alkyl.

R¹³ is

C₁ -C₃ perfluoroalkyl, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, where thesubstituents are hydroxy, NR¹⁰ R¹¹, carboxy, phenyl or substitutedphenyl; phenyl or substituted phenyl where the substituents on thephenyl are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy orhydroxy;

where v is as defined above;

R⁴, R^(4b), R⁵ and R^(5a) are independently hydrogen, phenyl,substituted phenyl, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl, where thesubstituents on the alkyl or phenyl are from 1 to 5 of hydroxy, C₁ -C₆alkoxy, C₃ -C₇ cycloalkyl, fluoro, R¹, R² independently disubstitutedphenyl C₁ -C₃ alkoxy, R¹, R² independently disubstituted phenyl, C₁ -C₂₀-alkanoyloxy, C₁ -C₅ alkoxycarbonyl, carboxy or formyl;

R⁴ and R⁵ can be taken together to form --(CH₂)_(r) --B--(CH₂)_(s) --where B is CHR¹, O, S(O)_(m) or N--R¹⁰, r and s are independently 1 to 3and R¹ and R¹⁰ are as defined above;

R⁶ is hydrogen, C₁ -C₁₀ alkyl or phenyl C₁ -C₁₀ alkyl;

A is ##STR6## where x and y are independently 0-2; R⁸ and R^(8a) areindependently hydrogen, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl wherethe substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy,fluoro, S(O)_(m) R^(7a), C₁ -C₆ alkoxy, R¹, R² independentlydisubstituted phenyl, C₁ -C₅ -alkanoyloxy, C₁ -C₅ alkoxycarbonyl,carboxy, formyl, --NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are independentlyhydrogen, C₁ -C₆ alkyl or C₁ -C₅ alkanoyl-C₁ -C₆ alkyl;

or R⁸ and R^(8a) can be taken together to form --(CH₂)_(t) -- where t is2 to 4; and R⁸ and R^(8a) can independently be joined to one or both ofR⁴ and R⁵ to form alkylene bridges between the terminal nitrogen and thealkyl portion of the A group wherein the bridge contains from 1 to 5carbon atoms;

and pharmaceutically acceptable salts thereof.

Additional preferred compounds are realized in the above structuralformula when:

n is 0 or 1;

p is 0 to 2;

q is 0 to 2;

w is 0 or 1;

X is S(O)_(m) or --CH═CH--;

m is 0 or 1;

R¹, R², R^(1a), R^(2a), R^(1b), and R^(2b) are independently hydrogen,halogen, C₁ -C₇ alkyl, C₁ -C₃ perfluoroalkyl, --S(O)_(m) R^(7a), R^(7b)O(CH₂)_(v) --, R^(7b) COO(CH₂)_(v) --, R^(7b) OCO(CH₂)_(v) --, phenyl orsubstituted phenyl where the substituents are from 1 to 3 of halogen, C₁-C₆ alkyl, C₁ -C₆ alkoxy, or hydroxy;

R^(7a) and R^(7b) are independently hydrogen, C₁ -C₆ alkyl orsubstituted C₁ -C₆ alkyl where the substituents are phenyl and v is 0 to2;

R^(3a) and R^(3b) are independently hydrogen, R⁹, C₁ -C₆ alkylsubstituted with R⁹, phenyl substituted with R⁹ or phenoxy substitutedwith R⁹ with the proviso that either R^(3a) or R^(3b) must be asubstituent other than hydrogen;

R⁹ is

R^(4b) R^(12b) NCON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12b) NCSN(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))CON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))COO(CH₂)_(v) --,

R^(4b) R^(12b) NCOO(CH₂)_(v) -- or R¹³ OCON(R^(12a))(CH₂)_(v) --,

where v is 0 to 2.

R^(12a), R^(12b) and R^(12c) are independently R^(5a), OR^(5a), orCOR^(5a). R^(12a) and R^(12b), or R^(12b) and R^(12c), or R^(12a) andR^(12c), or R^(12b) and R^(4b), or R^(12c) and R^(4b), or R¹³ andR^(12a) can be taken together to form --(CH₂)_(r) --B--(CH₂)_(s) --where B is CHR¹, O, S(O)_(m) or NR¹⁰, m is 0, 1 or 2, r and s areindependently 0 to 2, R¹ is as defined above and R¹⁰ is hydrogen, C₁ -C₆alkyl or C₁ -C₅ alkanoyl-C₁ -C₆ alkyl;

R¹³ is

C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, where the substituents arephenyl or substituted phenyl; phenyl or substituted phenyl where thesubstituents on the phenyl are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁-C₆ alkoxy or hydroxy;

R⁴, R^(4b), R⁵ and R^(5a) are independently hydrogen, C₁ -C₁₀ alkyl,substituted C₁ -C₁₀ alkyl, where the substituents on the alkyl are from1 to 5 of hydroxy, C₁ -C₆ alkoxy, fluoro, R¹, R² independentlydisubstituted phenyl, C₁ -C₂₀ -alkanoyloxy, C₁ -C₅ alkoxycarbonyl orcarboxy;

R⁶ is hydrogen or C₁ -C₁₀ alkyl;

A is ##STR7## where x and y are independently 0-2; R⁸ and R^(8a) areindependently hydrogen, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl wherethe substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy,fluoro, S(O)_(m) R^(7a), C₁ -C₆ alkoxy, R¹, R² independentlydisubstituted phenyl, C₁ -C₅ -alkanoyloxy, C₁ -C₅ alkoxycarbonyl,carboxy; or R⁸ and R^(8a) can be taken together to form --(CH₂)_(t) --where t is 2; or R⁸ and R^(8a) can independently be joined to one orboth of R⁴ and R⁵ to form alkylene bridges between the terminal nitrogenand the alkyl portion of the A group wherein the bridge contains from 1to 5 carbon atoms;

and pharmaceutically acceptable salts thereof.

Still further preferred compounds of the instant invention are realizedin the above structural formula when;

n is 0 or 1;

p is 0 to 2;

q is 1;

w is 1;

X is S(O)_(m) or --CH═CH--;

m is 0 or 1;

R¹, R², R^(1a), R^(2a), R^(1b) and R^(2b) are independently hydrogen,halogen, C₁ -C₇ alkyl, C₁ -C₃ perfluoroalkyl, --S(O)_(m) R^(7a), R^(7b)O(CH₂)_(v) --, R^(7b) COO(CH₂)_(v) --, phenyl or substituted phenylwhere the substituents are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆alkoxy or hydroxy;

R^(7a) and R^(7b) are independently hydrogen, C₁ -C₆ alkyl, substitutedC₁ -C₆ alkyl, where the substituents are phenyl and v is 0 or 1;

R^(3a) and R^(3b) are independently hydrogen, R⁹, or C₁ -C₆ alkylsubstituted with R⁹ with the proviso that either R^(3a) or R^(3b) mustbe a substituent other than hydrogen;

R⁹ is

R^(4b) R^(12b) NCON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))CON(R^(12a))(CH₂)_(v) --,

R^(4b) R^(12c) NN(R^(12b))COO(CH₂)_(v) --,

R^(4b) R^(12b) NCOO(CH₂)_(v) -- or R¹³ OCON(R^(12a))(CH₂)_(v) --,

where v is 0 or 1.

R^(12a), R^(12b) and R^(12c) are independently R^(5a), OR^(5a), orCOR^(5a). R^(12a) and R^(12b), or R^(12b) and R^(12c), or R^(12a) andR^(12c), or R^(12b) and R^(4b), or R^(12c) and R^(4b), or R¹³ andR^(12a) can be taken together to form --(CH₂)_(r) --B--(CH₂)_(s) --where B is CHR¹, O, S(O)_(m) or NR¹⁰, m is 0, 1 or 2, r and s areindependently 0 to 2, R¹ is as defined above and R¹⁰ is hydrogen, C₁ -C₆alkyl or C₁ -C₅ alkanoyl-C₁ -C₆ alkyl;

R¹³ is

C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, where the substituents arephenyl or substituted phenyl; phenyl or substituted phenyl where thesubstituents on the phenyl are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁-C₆ alkoxy or hydroxy;

R⁴, R^(4b), R⁵ and R^(5a) are independently hydrogen, C₁ -C₁₀ alkyl,substituted C₁ -C₁₀ alkyl, where the substituents on the alkyl are from1 to 3 of hydroxy, C₁ -C₃ alkoxy, fluoro, R¹, R² independentlydisubstituted phenyl, C₁ -C₂₀ alkanoyloxy, C₁ -C₅ alkoxycarbonyl orcarboxy;

R⁶ is hydrogen;

A is ##STR8## where x and y are independently 0-1; R⁸ and R^(8a) areindependently hydrogen, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl wherethe substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy,fluoro, S(O)_(m) R^(7a), C₁ -C₆ alkoxy, R¹, R² independentlydisubstituted phenyl, C₁ -C₅ -alkanoyloxy, C₁ -C₅ alkoxycarbonyl,carboxy; or R⁸ and R^(8a) can be taken together to form --(CH₂)_(t) --where t is 2; and R⁸ and R^(8a) can independently be joined to one orboth of R⁴ and R⁵ to form alkylene bridges between the terminal nitrogenand the alkyl portion of the A group wherein the bridge contains from 1to 5 carbon atoms;

and pharmaceutically acceptable salts thereof.

Representative preferred growth hormone releasing compounds of thepresent invention include the following:

1. N- 1- 2'- (Methoxycarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

2. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

3. N- 1- 2'- (Ethylaminocarbonyl)amino!1,1'-bphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

4. N- 1- 2'- (2-Propylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

5. N- 1- 2'- (Aminocarbonyl)amino!1,1'-biphenyl!-4-yl!-methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

6. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

7. N- 1- 2'- (Piperazinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

8. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

9. N- 1- 2'- (2-Hydroxypropylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

10. N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

11. N- 1- 2'- (Dimethylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

12. N- 1- 2'- (2(R)-Hydroxypropylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

13. N- 1- 2'- (2(S)-Hydroxypropylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

14. N- 1- 2'- 1-Hydroxyprop-2(R)-yl!amino!carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

15. N- 1- 2'- 4- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-(R)-yl!-3-amino-3-methylbutanamide;

16. N- 1- 2'- 2- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

17. N- 1- 2'- (Aminocarbonyl )amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

18. N- 1- 2'- (Aminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide;

19. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

20. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S)-hydroxypropyl!amino-3-methylbutanamide;

21. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide;

22. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

23. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide;

24. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

25. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S)-hydroxypropyl!amino-3-methylbutanamide;

26. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide;

27. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

28. N- 1- 2'- (Aminocarbonyl)amino!1,1'-biphenyl!-4-yl!-methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

29. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

30. N- 1- 2'- (Piperazinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

31. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

32. N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

33. N- 1- 2'- (Methoxycarbonylmethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

34. N- 1- 2'- (Hydroxyaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

35. N- 1- 2'- (Methoxycarbonyl)amino!1,1'-biphenyl!-4-yl!-methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

36. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

37. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

38. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

39. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

40. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

41. N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

42. N- 1- 2'- 2- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide;

43. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

44. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide;

45. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

46. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide;

47. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

48. N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

49. N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

50. N- 1- 2'- (Piperazinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

51. N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

52. N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide;

53. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

54. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

55. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

56. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

57. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

58. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

59. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

60. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

61. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

62. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

63. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

64. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

65. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

66. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

67. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

68. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

69. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

70. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

71. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

72. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

73. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

74. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

75. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

76. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

77. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

78. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

79. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

80. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

81. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

82. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

83. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

84. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

85. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

86. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

87. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

88. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

89. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

90. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

91. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

92. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

93. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

94. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

95. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

96. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

97. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

98. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

99. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

100. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

101. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

102. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

103. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

104. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

105. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

106. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

107. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

108. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

109. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

110. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

111. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

112. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

113. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

114. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

115. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

116. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

117. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

118. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

119. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

120. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

121. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

122. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

123. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3-(R)-yl!butanamide;

124. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

125. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

126. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

127. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

128. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

129. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

130. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

131. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

132. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

133. N- 5- 2'- (Methoxycarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-amino-3-methylbutanamide;

134. N- 5- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-amino-3-methylbutanamide;

135. N- 5- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-amino-3-methylbutanamide;

136. N- 5- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-amino-3-methylbutanamide;

137. N- 5- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

138. N- 5- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

139. N- 5- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide;

140. N- 5- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide;

141. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

142. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

143. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

144. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

145. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

146. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

147. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

148. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

149. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

150. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

151. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

152. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

153. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

154. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

155. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

156. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

157. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

158. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

159. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

160. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

161. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

162. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

163. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

164. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

165. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

166. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

167. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

168. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

169. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

170. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

171. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

172. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

173. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

174. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

175. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

176. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

177. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

178. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

179. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

180. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

181. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

182. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

183. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

184. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

185. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

186. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

187. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

188. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

189. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

190. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

191. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

192. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

193. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

194. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

195. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

196. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

197. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

198. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

199. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

200. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

201. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

202. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

203. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

204. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

205. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

206. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

207. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

208. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

209. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

210. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

211. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

212. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

213. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

214. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

215. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

216. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

217. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzo-thiazepin-3(S)-yl!butanamide;

218. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methoxy-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

219. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-methylthio-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

220. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-trifluoromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

221. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'- 2-(methylamino)carbonyl!amino!prop-2-yl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

222. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'- 1-(methylamino)carbonyl!amino!ethyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

223. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

224. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

225. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

226. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

227. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

228. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

229. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2 '-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

230. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

231. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;

232. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

233. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

234. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;

235. 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide;

236. 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

237. 3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide;

238. 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5-2'- (methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide.

Representative examples of the nomenclature employed are given below:

N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide##STR9## N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!-4-yl!methyl!-7-methyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-2-amino-2-methylpropanamide##STR10## N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide ##STR11## 3-2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'- 2-4-morpholinocarbonyl!amino!ethyl!1,1'-biphenyl!-4-yl!methyl!-7-methyl-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide##STR12##

The compounds of the instant invention all have at least one asymmetriccenter as noted by the asterisk in the structural Formula I above.Additional asymmetric centers may be present on the molecule dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will produce two optical isomers and it is intendedthat all such optical isomers, as separated, pure or partially purifiedoptical isomers or racemic mixtures thereof, be included within theambit of the instant invention. In the case of the asymmetric centerrepresented by the asterisk in Formula I, it has been found that thecompound in which the 3-amino substituent is above the plane of thestructure, as seen in Formula Ia, is more active and thus more preferredover the compound in which the 3-amino substituent is below the plane ofthe structure. In the substituent (X)_(n), when n=0, the asymmetriccenter is designated as the R-isomer. When n=1, this center will bedesignated according to the R rules as either R or S depending upon thevalue of X. ##STR13##

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable acid addition salts, such as the saltsderived from using inorganic and organic acids. Examples of such acidsare hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,trifluoroacetic, propionic, maleic, succinic, malonic and the like. Inaddition, certain compounds containing an acidic function such as acarboxy can be isolated in the form of their inorganic salt in which thecounterion can be selected from sodium, potassium, lithium, calcium,magnesium and the like, as well as from organic bases.

The compounds (I) of the present invention are prepared from aminolactamintermediates such as those of formula II. The preparation of theseintermediates is described in the following reaction Schemes. ##STR14##

Benzo-fused lactams 3 wherein the lactam is a seven-membered ring areconveniently prepared from substituted tetralones 2 using knownprocedures. The substituted tetralones are, in some cases, commerciallyavailable or are prepared from a suitably substituted derivative of4-phenylbutyric acid 1. Cyclization of 1 can be achieved by a number ofmethods well known in the literature including treatment withpolyphosphoric acid at elevated temperatures as shown in Scheme 1.##STR15##

Conversion of substituted tetralones 2 to benzolactams 3 can be achievedby a number of methods familiar to those skilled in the art. A suitablemethod involves the use of hydrazoic acid (Schmidt or Curtius reactions)to form the substituted benzolactam 3.

Benzo-fused lactams wherein the lactam is an eight-membered ring (6) areprepared as described by D. H. Jones, et al, J. Chem. Soc. C, 2176-2181(1969) by a series of analogous transformations starting from asubstituted derivative of 5-phenylpentanoic acid 4 as shown in Scheme 2.##STR16##

As illustrated in Scheme 3, an analogous sequence is employed in theconstruction of benzo-fused lactams containing nine-membered rings. Therequisite benzocyclooctanone intermediate 8 is obtained byacid-catalyzed cyclization of the substituted 6-phenylhexanoic acidprecursor 7 using the aforementioned conditions. Elaboration to thedesired nine-membered lactam product 9 can be achieved directly, throughthe use of hydrazoic acid (Schmidt reaction) using conditions describedby R. Huisgen, et al, Ann., 586, 30-51 (1954); or, via Beckmannrearrangement of an intermediate oxime, as demonstrated by W. M.Schubert, et al, J. Amer. Chem. Soc., 76, 5462-5465 (1954). ##STR17##

As shown in Scheme 4, 3-aminobenzolactam analogs wherein the lactam is asix-membered ring (14) are prepared from a substituted derivative of2-nitrobenzyl chloride (or bromide) 10 by the method of A. L. Davis, etal, Arch. Biochem. Biophys., 102, 48-51 (1963) and references citedtherein. ##STR18##

Benzo-fused aminolactam analogs containing a five-membered lactam areprepared by an analogous sequence from appropriately substitutedderivatives of ethyl o-nitromandelate 15 by the procedure of A. L.Davis, et al, J. Med. Chem., 16, 1043-1045 (1973), as shown in Scheme 5.##STR19##

Conversion of substituted benzo-fused lactams to the requisite 3-aminoderivatives can be achieved by a number of methods familiar to thoseskilled in the art, including those described by Watthey, et al, J. Med.Chem., 28, 1511-1516 (1985) and references cited therein. One commonroute proceeds via the intermediacy of a 3-halo (chloro, bromo or iodo)intermediate which is subsequently displaced by a nitrogen nucleophile,typically azide. A useful method of forming the 3-iodobenzolactamintermediate 20 involves treating the benzolactam with two equivalentseach of iodotrimethylsilane and iodine at low temperature, asillustrated in Scheme 6 for the seven-membered ring analog 3. ##STR20##

Elaboration of the iodobenzolactams to the desired aminolactamintermediate II is achieved by a two-step procedure illustrated inScheme 6. Typically, iodobenzolactam 20 is treated with sodium azide inN,N-dimethylformamide at 50°-100° C. to give the 3-azido derivative 21.Alternatively, tetramethylguanidinium azide in a solvent such asmethylene chloride can be employed to achieve similar results.Hydrogenation with a metal catalyst, such as platinum on carbon, oralternatively, treatment with triphenylphosphine in wet toluene, resultsin formation of the amine derivative 22. Formation of the analogousderivatives of the eight- and nine-membered benzolactams is alsoachieved by the routes shown in Scheme 6.

Chiral aminobenzolactams are obtained by resolution of the racemates byclassical methods familiar to those skilled in the art. For example,resolution can be achieved by formation of diastereomeric salts of theracemic amines with optically active acids such as D- and L-tartaricacid. Determination of absolute stereochemistry can be achieved in anumber of ways including X-ray analysis of a suitable crystallinederivative.

A useful preparation of the chiral intermediate 27 is shown in Scheme 7.##STR21##

Conversion of 1-tetralone to the seven-membered benzolactam 24 isachieved by Beckman rearrangement of the intermediate oxime 23.Treatment of 24 with iodine and hexamethyldisilazane gives the 3-iododerivative 25 which is sequentially treated with ammonia and D-tartaricacid to give the diastereomeric D-tartrate salt 26 afterrecrystallization. Liberation of the free amine 27 is achieved byneutralization of the D-tartrate salt with potassium carbonate followedby extractive isolation.

Intermediates of Formula II wherein X is a sulfur atom are prepared bymethods described in the literature and known to those skilled in theart. As illustrated in Scheme 8, the seven-membered ring analog 35 isprepared from a protected derivative of cysteine 29 by the method ofSlade, et al, J. Med. Chem., 28, 1517-1521 (1985) and references citedtherein (CBz is benzyloxycarbonyl). ##STR22##

Sulfoxide and sulfone intermediates 36 and 37 are prepared by oxidationof 32 with various oxidants such as sodium periodate ormeta-chloroperbenzoic acid. Eight-membered ring intermediates of FormulaII wherein X is sulfur can be prepared by an analogous route startingfrom derivatives of homo-cysteine.

Intermediates of Formula II wherein X is an oxygen atom are prepared bymethods described in the literature and known to those skilled in theart. For example, the seven-membered ring analog 39 can be prepared froma substituted derivative of 3-(2-nitrophenoxy)propanoic acid 38 by themethod of J. Ott, Arch. Pharm. (Weinheim, Ger.), 323(9), 601-603 (1990).##STR23##

Six-membered ring analogs wherein X is oxygen (41) may be prepared byreaction of a substituted derivative of 2-aminophenol 40 withchloroacetyl chloride by the method of Huang and Chan, Synthesis, 10,851 (1984) and references cited therein. Subsequent incorporation of anamino group at the 3 position of either 39 or 41 is achieved by themethods described in Scheme 6. ##STR24##

Seven-membered ring analogs of Formula II wherein X is C═O can beprepared from derivatives of tryptophan as described in the AustralianJ. Chem., 33, 633-640 (1980). Seven-membered ring analogs of Formula IIwherein X is CH═CH can be prepared from the aforementioned analogswherein X is C═O. Treatment of 42 with chemical reducing agents such assodium borohydride in a polar solvent such as methanol or ethanolresults in reduction to give the secondary alcohol derivative 43(X═CHOH). ##STR25##

Dehydration of 43 can be achieved by several methods decribed in theliterature and familiar to those skilled in the art. For example,treatment of 43 in an inert solvent, such as benzene, with a strong acidsuch as p-toluenesulfonic acid, can result in dehydration to theunsatured analog 44. ##STR26##

Intermediates of formula II can be further elaborated to newintermediates (formula III) which are substituted on the amino group(Scheme 11). Reductive alkylation of II with an aldehyde is carried outunder conditions known in the art; for example, by catalytichydrogenation with hydrogen in the presence of platinum, palladium ornickel catalysts or with chemical reducing agents such as sodiumcyanoborohydride in an inert solvent such as methanol or ethanol.##STR27##

Attachment of the amino acid sidechain to intermediates of formula IIIis accomplished by the route shown in Scheme 12. Coupling isconveniently carried out by the use of an appropriately protected aminoacid derivative, such as that illustrated by formula IV, and a couplingreagent such as benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate ("BOP") orbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate("PyBOP") in an inert solvent such as methylene chloride. Separation ofunwanted side products, and purification of intermediates is achieved bychromatography on silica gel, employing flash chromatography (W. C.Still, M. Kahn and A. Mitra, J. Org. Chem., 43, 2923 (1978)) or bymedium pressure liquid chromatography. ##STR28##

The protected amino acid derivatives IV are, in many cases, commerciallyavailable in t-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBz) forms. Auseful method to prepare the preferred sidechain 49 is shown in Scheme13. ##STR29##

Reaction of isobutylene with N-chlorosulfonylisocyanate 45 in diethylether gives the azetidinone derivative 46. Removal of the chlorosulfonylgroup with aqueous sodium sulfite followed by reaction withdi-t-butyldicarbonate gives the BOC-protected intermediate 48. Alkalinehydrolysis gives the protected amino acid derivative 49 in good overallyield.

Intermediates of formula VII are prepared as shown in Scheme 14 bytreatment of the desired lactam intermediate V with an alkylating agentVI, wherein Y is a good leaving group such as Cl, Br, I,O-methanesulfonyl or O-(p-toluenesulfonyl). Alkylation of intermediatesof formula V is conveniently carried out in anhydrous dimethyl formamide(DMF) in the presence of bases such as sodium hydride or potassiumt-butoxide for a period of 0.5 to 24 hours at temperatures of 20°-100°C. Substituents on the alkylating agent VI may need to be protectedduring alkylation. A description of such protecting groups may be foundin: Protective Groups in Organic Synthesis, T. W. Greene, John Wiley andSons, New York, 1981. ##STR30##

Alkylating agents VI are in some cases commercially available or may beprepared by methods described in the literature and familiar to oneskilled in the art. Compounds of formula I where R^(3a) or R^(3b) is acarbamate, semicarbazide or urea derivative, wherein this functionalityis attached to the phenyl ring by a nitrogen atom are prepared fromintermediate 50, obtained by alkylation with a derivative of formula VIwherein R^(3a) or R^(3b) is a nitro group as shown in Scheme 15.##STR31##

A useful method of synthesizing a preferred alkylating agent 54 is shownin reaction Scheme 16. ##STR32##

Reaction of 4-tolylboronic acid 51 with 2-bromonitrobenzene 52 in thepresence of a transition metal catalyst such as(tetrakis)triphenylphosphine palladium (0) in a mixed solvent systemcontaining aqueous sodium hydroxide, water, 2-propanol and benzene atelevated temperatures for several hours gives the coupled product 53 ingood overall yield. Chromatographic purification and separation ofunwanted by-products is conveniently performed on silica, eluting withcommon organic solvents such as hexane, ethyl acetate and methylenechloride. Conversion of 53 to the bromide derivative 54 is accomplishedby treatment with N-bromosuccinimide in refluxing carbon tetrachloridein the presence of a radical initiator such as benzoyl peroxide or2,2'-azobisisobutyronitrile (AIBN).

As shown in Scheme 17, reduction of the nitro group of 50 is achieved byhydrogenation in the presence of a metal catalyst, such as palladium oncarbon, in a protic solvent such as methanol or ethanol. It may beappreciated by one skilled in the art that for certain compounds wherecatalytic hydrogenation is incompatible with existing functionality,alternative methods of reduction are indicated, such as chemicalreduction with stannous chloride under acidic conditions. It should alsobe noted that the protecting group G in intermediate 50 must becompatible with the experimental conditions anticipated for reduction.For example, intermediate 50 wherein G is t-butoxycarbonyl (BOC) isstable to the conditions of catalytic reduction employed in theconversion to 55. Intermediate 55 may also be further elaborated to anew intermediate 56 by reductive alkylation with an aldehyde by theaforementioned procedures. ##STR33##

Elaboration of 56 to carbamate compound 57 is achieved by reaction withthe appropriate chloroformate reagent in pyridine or in methylenechloride with triethylamine as shown in Scheme 18. ##STR34##

Transformation of amine intermediate 56 to urea derivatives isaccomplished in several ways. Terminally disubstituted compounds can beobtained directly by reaction of 56 with a disubstituted carbamoylchloride 58 in an inert solvent such as methylene chloride in thepresence of triethylamine or 4-dimethylaminopyridine. In addition,mono-substituted compound 61 wherein either R^(4b) or R^(12b) ishydrogen is obtained from 56 by reaction with an isocyanate 60 as shownin Scheme 19. Terminally unsubstituted urea 61, wherein R^(12b) ishydrogen, is also prepared from amine 56 by reaction with trimethylsilylisocyanate (60; R^(12b) is (CH₃)₃ Si). ##STR35##

Alternatively, amine 55 is converted to an isocyanate 62 by treatmentwith phosgene or an equivalent reagent such asbis(trichloromethyl)carbonate (triphosgene) as indicated in Scheme 20.Subsequent reaction of 62 with primary or secondary amines in an inertsolvent such as methylene chloride gives the corresponding ureaderivative 59 in good yield. Isocyanate 62 is also converted tosubstituted semicarbazides 63 or hydroxy- or alkoxyureas 64 by reactionwith substituted hydrazines or hydroxy- or alkoxylamines, respectively.##STR36##

Compounds of formula I where R^(3a) or R^(3b) is a carbazate orcarbamate derivative where attachment to the phenyl ring is through theoxygen atom of the carbazate or carbamate linkage are prepared fromacetophenone intermediate 65 as indicated in Scheme 21. ##STR37##

Oxidative rearrangement of 65 through the use of a peroxy-carboxylicacid (Baeyer-Villager reaction) such as m-chloroperbenzoic acid givesthe ester 66 which is hydrolyzed in the presence of a strong base suchas sodium or lithium hydroxide to give phenol 67. Reaction of 67 with anisocyanate leads directly to carbamate 68. Additionally, treatment of 67with N,N'-carbonyldiimidazole in dimethylformamide can form an activatedintermediate which will react with substituted hydrazine reagents togive a carbazate product 69.

Compounds of formula I wherein R^(3a) or R^(3b) is R^(4b) R^(12b)NCON(R^(12a))CH₂ --, R^(4b) R^(12b) NCSN(R^(12a))CH₂ --, R^(4b) R^(12c)NN(R^(12b))CSN(R^(12a))CH₂ --, R^(4b) R^(12c)NN(R^(12b))--CON(R^(12a))CH₂ -- or R¹³ OCON(R^(12a))CH₂ -- can beprepared from the t-butyl ester intermediate 70 as described in Scheme22. Removal of the t-butyl ester through the use of trifluoroacetic acidwill give the carboxylic acid 71. It may be appreciated by one skilledin the art that the protecting group G in 70 must therefore becompatible with the strongly acidic conditions employed for estercleavage; hence G is taken as benzyloxycarbonyl. Conversion of thecarboxylic acid to the benzylamine derivative 72 can be achieved by afive-step sequence consisting of: 1) formation of a mixed anhydride withisobutyl chloroformate; 2) reduction with sodium borohydride to thebenzyl alcohol; 3) formation of the mesylate with methanesulfonylchloride; 4) formation of the azide by reaction with sodium azide, andfinally, 5) reduction of the azide with tin(II) chloride. Thebenzylamine intermediate 72 can be further elaborated to 73 by theaforementioned reductive amination procedure. ##STR38##

Reactions of amine 73 with the appropriate reagents to form urea-linkedcompounds 74 and 75 and carbamate-linked compound 76 are illustrated inScheme 23. Terminally unsubstituted urea 74, wherein R^(12b) ishydrogen, is also prepared from amine 73 by reaction with trimethylsilylisocyanate (60; R^(12b) is (CH₃)₃ Si). ##STR39##

As shown in Scheme 24, hydrazide compound 77 can be prepared fromintermediate 73 by a two-step procedure consisting of activation of theamine via treatment with N,N'-carbonyldiimidazole followed by treatmentwith the appropriately substituted hydrazine derivative R^(4b) R^(12c)NN(R^(12b))H. ##STR40##

A useful preparation of the protected benzylamine intermediate 82 isshown in Scheme 25. Metallation of 4-bromobenzylt-butyldiphenylsilylether 78 with n-butyllithium followed by treatmentwith triisopropyl borate gives the aryl boronic acid 79. Reaction of 79with 2-bromo- N-(t-butoxycarbonyl)benzylamine 80 in the presence oftetrakis(triphenylphosphine)palladium(0) and sodium hydroxide in a mixedsolvent system at elevated temperature gives the coupled product 81 ingood yield. Desilylation and conversion to the O-methanesulfonate 82 isachieved by treatment with tetrabutylammonium fluoride followed bymethanesulfonyl chloride. Reaction of 82 with compounds of formula V iscarried out using the conditions described in Scheme 14. ##STR41##

Conversion to the final products of formula I wherein R⁴ is hydrogen, iscarried out by simultaneous or sequential removal of all protectinggroups from intermediate VII as illustrated in Scheme 26. ##STR42##

Removal of benzyloxycarbonyl (CBz) groups can be achieved by a number ofmethods known in the art; for example, catalytic hydrogenation withhydrogen in the presence of a platinum or palladium catalyst in a proticsolvent such as methanol. In cases where catalytic hydrogenation iscontraindicated by the presence of other potentially reactivefunctionality, removal of benzyloxycarbonyl groups can also be achievedby treatment with a solution of hydrogen bromide in acetic acid. Removalof t-butoxycarbonyl (BOC) protecting groups is carried out by treatmentof a solution in a solvent such as methylene chloride or methanol, witha strong acid, such as hydrochloric acid or trifluoroacetic acid.Conditions required to remove other protecting groups which may bepresent can be found in Protective Groups in Organic Synthesis T. W.Greene, John Wiley and Sons, New York. 1981.

As shown in Scheme 27, compounds of formula I wherein R⁴ and R⁵ are eachhydrogen can be further elaborated by reductive alkylation with analdehyde by the aforementioned procedures or by alkylations such as byreaction with various epoxides. The products, obtained as hydrochlorideor trifluoroacetate salts, are conveniently purified by reverse phasehigh performance liquid chromatography (HPLC) or by recrystallization.##STR43##

It is noted that the order of carrying out the foregoing reactionschemes is not significant and it is within the skill of one skilled inthe art to vary the order of reactions to facilitate the reaction or toavoid unwanted reaction products.

The growth hormone releasing compounds of Formula I are useful in vitroas unique tools for understanding how growth hormone secretion isregulated at the pituitary level. This includes use in the evaluation ofmany factors thought or known to influence growth hormone secretion suchas age, sex, nutritional factors, glucose, amino acids, fatty acids, aswell as fasting and non-fasting states. In addition, the compounds ofthis invention can be used in the evaluation of how other hormonesmodify growth hormone releasing activity. For example, it has alreadybeen established that somatostatin inhibits growth hormone release.Other hormones that are important and in need of study as to theireffect on growth hormone release include the gonadal hormones, e.g.,testosterone, estradiol, and progesterone; the adrenal hormones, e.g.,cortisol and other corticoids, epinephrine and norepinephrine; thepancreatic and gastrointestinal hormones, e.g., insulin, glucagon,gastrin, secretin; the vasoactive intestinal peptides, e.g., bombesin;and the thyroid hormones, e.g., thyroxine and triiodothyronine. Thecompounds of Formula I can also be employed to investigate the possiblenegative or positive feedback effects of some of the pituitary hormones,e.g., growth hormone and endorphin peptides, on the pituitary to modifygrowth hormone release. Of particular scientific importance is the useof these compounds to elucidate the subcellular mechanisms mediating therelease of growth hormone.

The compounds of Formula I can be administered to animals, includingman, to release growth hormone in vivo. For example, the compounds canbe administered to commercially important animals such as swine, cattle,sheep and the like to accelerate and increase their rate and extent ofgrowth, and to increase milk production in such animals. In addition,these compounds can be administered to humans in vivo as a diagnostictool to directly determine whether the pituitary is capable of releasinggrowth hormone. For example, the compounds of Formula I can beadministered in vivo to children. Serum samples taken before and aftersuch administration can be assayed for growth hormone. Comparison of theamounts of growth hormone in each of these samples would be a means fordirectly determining the ability of the patient's pituitary to releasegrowth hormone.

Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of Formula I in association with apharmaceutical carrier or diluent. Optionally, the active ingredient ofthe pharmaceutical compositions can comprise a growth promoting agent inaddition to at least one of the compounds of Formula I or anothercomposition which exhibits a different activity, e.g., an antibiotic orother pharmaceutically active material.

Growth promoting agents include, but are not limited to, TRH,diethylstilbesterol, theophylline, enkephalins, E series prostaglandins,compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, andcompounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox orpeptides disclosed in U.S. Pat. No. 4,411,890.

A still farther use of the disclosed novel benzo-fused lactam growthhormone secretagogues is in combination with other growth hormonesecretagogues such as GHRP-6, GHRP-1 or GHRP-2 as described in U.S. Pat.No. 4,411,890; and publications WO 897110 and WO 89/07111 and B-HT 920or in combination with growth hormone releasing factor and its analogsor growth hormone and its analogs. A still further use of the disclosednovel benzo-fused lactam growth hormone secretagogues is in combinationwith α₂ adrenergic agonists or β₃ adrenergic agonists in the treatmentof obesity or in combination with parathyroid hormone orbisphosphonates, such as MK-217 (alendronate), in the treatment ofosteoporosis. A still further use of the disclosed novel benzo-fusedlactam growth hormone secretagogues is in combination with IGF-1 toreverse the catabolic effects of nitrogen wasting as described byKupfer, et al, J. Clin. Invest., 91, 391 (1993).

As is well known to those skilled in the art, the known and potentialuses of growth hormone are varied and multitudinous. Thus, theadministration of the compounds of this invention for purposes ofstimulating the release of endogenous growth hormone can have the sameeffects or uses as growth hormone itself. These varied uses of growthhormone may be summarized as follows: stimulating growth hormone releasein elderly humans; prevention of catabolic side effects ofglucocorticoids; treatment of osteoporosis; stimulation of the immunesystem; treatment of retardation; acceleration of wound healing;accelerating bone fracture repair; treatment of growth retardation,treating renal failure or insufficiency resulting in growth retardation;treatment of physiological short stature, including growth hormonedeficient children; treating short stature associated with chronicillness; treatment of obesity and growth retardation associated withobesity; treating growth retardation associated with Prader-Willisyndrome and Turner's syndrome; accelerating the recovery and reducinghospitalization of burn patients; treatment of intrauterine growthretardation, skeletal dysplasia, hypercortisolism and Cushings syndrome;induction of pulsatile growth hormone release; replacement of growthhormone in stressed patients; treatment of osteochondrodysplasias,Noonans syndrome, schizophrenia, depression, Alzheimer's disease,delayed wound healing, and psychosocial deprivation; treatment ofpulmonary dysfunction and ventilator dependency; attenuation of proteincatabolic response after a major operation; reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS. Treatment ofhyperinsulinemia including nesidioblastosis; adjuvant treatment forovulation induction; to stimulate thymic development and prevent theage-related decline of thymic function; treatment of immunosuppressedpatients; improvement in muscle strength, mobility, maintenance of skinthickness, metabolic homeostasis, renal hemeostasis in the frailelderly; stimulation of osteoblasts, bone remodelling, and cartilagegrowth; stimulation of the immune system in companion animals andtreatment of disorders of aging in companion animals; growth promotantin livestock and stimulation of wool growth in sheep.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous or subcutaneousinjection or implant), nasal, vaginal, rectal, sublingual, or topicalroutes of administration and can be formulated in dosage formsappropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., lubricating agents such as magnesium stearate. In thecase of capsules, tablets and pills, the dosage forms may also comprisebuffering agents. Tablets and pills can additionally be prepared withenteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, the elixirscontaining inert diluents commonly used in the an, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized by, forexample, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as cocoa butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. Generally, dosagelevels of between 0.0001 to 100 mg/Kg of body weight daily areadministered to patients and animals, e.g., mammals, to obtain effectiverelease of growth hormone.

The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

EXAMPLE 1 N- 1- 2'- (Methoxycarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

1-Tetralone oxime

To 4.6 L of water at room temperature in a 4-neck 50 L flask sitting ina steam bath apparatus equipped with an overhead stirrer, a temperatureprobe and reflux condenser was added 3.72 Kg (27.36 mol) of sodiumacetate with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride(27.36 mol). To this slurry at room temperature, 12 L of ethanol wasadded followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additionalethanol (1.7 L) was used to rinse off the funnel and added to thereaction mixture. The resulting light orange slurry was heated to 75° C.over 40 minutes and maintained at 75°-85° C. for another 75 minutes. Thereaction mixture was cooled with the aid of ice packed around the flask.When the internal temperature reached 32° C., the reaction mixture waspumped over 15 minutes into 60 L of ice contained in a 200 L vessel. Thereaction vessel was washed with an additional 2 L of water which wasadded to the 200 L vessel. When the ice melted, the mixture was filteredthrough a filter pad and the wet cake washed with 4 L of water. The wetcake was suction dried for 1 hour then transferred to two trays anddried under vacuum at 40° C. for 2 days to give 2.094 Kg (13.01 mol,95%) of product. ¹ H NMR (250 MHz, CDCl₃): δ 1.90 (m, 2H), 2.80 (t, 6Hz, 2H), 2.88 (t, 6 Hz, 2H), 7.15-7.35 (m, 3H), 7.90 (d, 8 Hz, 1H), 8.9(br s, 1H).

Step B:

2,3,4,5-Tetrahydro-1H-1-benzazepin-2-one

To 10 L of methanesulfonic acid in a 22 L 3-neck flask equipped with anoverhead stirrer, a temperature probe, nitrogen inlet and refluxcondenser, was added 2.6 Kg (18.61 mol) of phosphorus pentoxide. Anadditional 1.6 L of methanesulfonic acid was used to wash all thephosphorus pentoxide into the vessel. The mixture was heated at 90° C.for 2.5 hours then cooled to 50° C. using an ice bath and treated with2.00 Kg (12.41 mol) of 1-tetralone oxime in several portions over 15minutes. The mixture was heated at 63° C. for 10 minutes then slowlyheated to 80° C. and kept at 80° C. for 3 hours. The reaction mixturewas pumped into 70 L of ice then treated slowly with 11.25 L of 50%aqueous sodium hydroxide over 90 minutes at such a rate so as tomaintain the temperature below 28° C. The mixture was filtered and 4 Lof the filtrate was used to rinse the vessel. The wet cake (pink) waswashed with 8 L of water then suction dried for 45 minutes andtransferred to two trays and dried under vacuum at 40° C. for 2 days togive 1.9 Kg (11.79 mol,95%) of product. ¹ H NMR (250 MHz,CDCl₃): δ 2.24(m, 2H), 2.38 (t, 6 Hz, 2H), 2.82 (t, 6 Hz, 2H), 7.03 (d, 8 Hz, 1H),7.13 (m, 1H), 7.24 (m, 2H), 8.63 (br s, 1H).

Step C:

3-Iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

A suspension of 1.8 Kg (11.17mol) of2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in a mixture of 22.33 L ofmethylene chloride and 11.78 L (55.83 mol) of hexamethyldisilazane washeated at reflux for 10 minutes, then cooled to 30° C. and treated with8.503 Kg (33.5 mol) of iodine in one portion. The mixture was heated atreflux for 2.5 hours, then cooled to room temperature. Aqueous sodiumsulfite containing 4.926 Kg of sodium sulfite in 44 L of water wascooled to 0° C. and into it was poured the reaction mixture in severalportions with vigorous stirring while maintaining the temperature below10° C. The reaction vessel was rinsed with 22.33 L of methylene chlorideand the washing transferred to the quenching mixture. The quenchingmixture was stirred vigorously and the layers allowed to separate. Theaqueous layer was removed and reextracted with 22.33 L of methylenechloride. The combined organic layers were washed with 11 L of water andconcentrated under vacuum to a final volume of approximately 5 L. Theresidue was treated with 55 L of toluene and concentrated under vacuumto a final volume of 10 L. The resulting slurry was isolated byfiltration and the filter cake washed with an additional 5 L of tolueneand dried under vacuum at ambient temperature for 24 hours to give 1.842Kg (6.42 mol, 57%) of product. ¹ H NMR (200 MHz, CDCl₃): δ 2.6-2.8 (m,3H), 2.93 (m, 1H), 4.64 (t, 8 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.10-7.35 (m,3H), 7.55 (br s, 1H).

Step D:

3(R)-Amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, D-tartaric acidsalt

3-Iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (1.79 Kg, 6.24 mol) wasslurried in 6.2 L of methanol and the slurry charged into an autoclave.Condensed ammonia (1.55 L) was added and the autoclave closed, withstirring, and heated to 100° C. over 1 hour. Heating at 100° C. wascontinued for 2 hours then the autoclave was allowed to cool to roomtemperature over 1 hour, during which time the internal pressure was150-155 psi. The reaction mixture was transferred to a polyethylene jugand the autoclave rinsed with 2×8 L of methanol. The washings wereconcentrated under vacuum at 30° C. then combined with the reactionmixture and concentrated to near dryness under vacuum at 30° C. Theresulting residue was dissolved in 4 L of ethyl acetate thenconcentrated to dryness under vacuum at 30° C.

Sodium chloride (712 g) was dissolved in 2 L of water and 1.0 Kg ofsodium carbonate was dissolved in 6 L of water. Two liters of the sodiumcarbonate solution was added to the concentrated residue and theresulting slurry transferred to an extraction flask. Another 2 L portionof the sodium carbonate solution was added to the residue flask and thesolution transferred to the extraction flask. The remaining sodiumcarbonate solution was used in the same way. The sodium chloridesolution was added to the sodium carbonateminolactam emulsion and theresulting mixture stirred for 10 minutes then extracted with four 6 Lportions of methylene chloride. The combined methylene chloride layerswere concentrated to dryness; the residue was treated with 2 L of 200proof ethanol and the resulting slurry concentrated to dryness undervacuum to give 1.171 Kg of crude product.

The crude product was slurried in 8 L of ethanol and treated with 900 gof D-tartaric acid in one portion. Water (7 L) was added and the mixtureheated to 77° C., then additional ethanol (45 L) was added and heatingcontinued. The solution was cooled to 43° C. and treated with the seedslurry. (The seed slurry was prepared by the route described abovestarting with 10.50 g of crude product and 9.1 g of D-tartaric acid.)The solution was aged at room temperature for 48 hours. The slurryformed was removed by filtration and the wet cake washed with 1.8 L ofethanol. The resulting filter cake was suction dried with nitrogenbleeding for 20 hours, then transferred into a drying tray and driedunder vacuum for 24 hours to give 354 g (1.085 mol, 17.4%) of theproduct. ¹ H NMR (250 MHz, CDCl₃): δ 2.13 (m, 1H), 2.51 (m, 2H), 2.73(m, 2H), 3.68 (t, 6 Hz, 1H), 3.98 (s, 2H), 7.05 (d, 8 Hz, 1H), 7.16 (t,8 Hz, 1H), 7.30 (m, 2H), 7.6 (br s, 5H), 10.26 (br s, 1H).

Step E:

3(R)-Amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

A solution of 229.23 g (0.700 mol) of3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, D-tartrate in 4.1 Lof water was treated with 194 g (1.40 mol) of potassium carbonate.Subsequent portions of 100 g and 135 g of potassium carbonate were addeduntil the pH was 10.5. The mixture was extracted with four 4 L portionsof methylene chloride which were then combined and dried over magnesiumsulfate. The aqueous layer was treated with 1.4 Kg of sodium chlorideand reextracted with four 4 L portions of methylene chloride which werethen combined and dried over magnesium sulfate. The two 16 L batches ofextracts were combined, filtered and concentrated to dryness undervacuum to give 115.5 g of product which contained 1.6% of an impurityidentified as 7-iodo-3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one.

A solution of 107.02 g (0.607 mol) of the intermediate obtained above in1.712 L of ethanol was hydrogenated at room temperature and 40 psi over4.00 g of 10% palladium on carbon for 4 hours. The catalyst was removedby filtration through solkaflok and the filtrate concentrated to drynessunder vacuum to give 101.08 g (0.574 mol, 94.4%) of product.

Step F:

4,4-Dimethylazetidin-2-one

A 3-neck 3 L round bottom flask equipped with a magnetic stirrer,thermometer, cold finger condenser and nitrogen bubbler was charged with1 L of ether. The flask was cooled to -65° C. and into it was condensed500-600 mL of isobutylene. The cold finger condenser was replaced with adropping funnel and 200 mL (325 g, 2.30 mol) of chlorosulfonylisocyanate was added dropwise over 1.5 hours. The mixture was maintainedat -65° C. for 1.5 hours then the dry icecetone cooling bath replacedwith methanol/ice and the internal temperature slowly increased to -5°C. at which time the reaction initiated and the internal temperaturerose to 15° C. with evolution of gas. The internal temperature remainedat 15° C. for several minutes then dropped back down to -5° C. and themixture stirred at -5° C. for 1 hour. The methanol/ice bath was removedand the reaction mixture warmed to room temperature and stirredovernight.

The reaction mixture was transferred to a 3-neck 12 L round bottom flaskfitted with a mechanical stirrer and diluted with 2 L of ether. The wellstirred reaction mixture was treated with 2 L of saturated aqueoussodium sulfite. After 1 hour, an additional 1 L of saturated aqueoussodium sulfite was added followed by sufficient sodium bicarbonate toadjust the pH to approximately 7. The mixture was stirred another 30minutes then the layers allowed to separate. The ether layer was removedand the aqueous layer reextracted with 2×1 L of ether. The combinedether extracts were washed once with 500 mL of saturated aqueous sodiumbicarbonate and once with 500 mL of saturated aqueous sodium chloride.The ether layer was removed, dried over magnesium sulfate, filtered andconcentrated under vacuum to give 33 g of a pale yellow oil. The aqueouslayer was made basic by the addition of solid sodium bicarbonate andextracted with 3×1 L of ether. The combined ether extracts were washedand dried as described above, then combined with the original 33 g ofpale yellow oil and concentrated under vacuum to give 67.7 g of product.Further extraction of the aqueous layer with 4×1 L of methylene chlorideand washing and drying as before gave an additional 74.1 g of product.Still further extraction of the aqueous layer with 4×1 L of methylenechloride gave an additional 21.9 g of product. The combined product(163.7 g, 1.65 mol, 72%) was used in Step G without purification. ¹ HNMR (200 MHz, CDCl₃): δ 1.45 (s, 6H), 2.75 (d, 3 Hz, 2H), 5.9 (br s,1H).

Step G:

N-(t-Butoxycarbonyl)-4,4-dimethylazetidin-2-one

A 5 L, 3-neck round bottom flask equipped with a magnetic stirrer,thermometer, nitrogen bubbler and addition funnel was charged with 88.2g (0.89 mol) of 4,4-dimethylazetidin-2-one (Step F), 800 mL of methylenechloride, 150 mL of triethylamine (1.08 mol) and 10.9 g (0.089 mol) of4-dimethylaminopyridine. To the stirred solution, at room temperaturewas added dropwise over 15 minutes a solution of 235 g (1.077 mol) ofdi-t-butyl-dicarbonate in 300 mL of methylene chloride. The reactionmixture was stirred at room temperature overnight, then diluted with 1 Lof methylene chloride and washed with 500 mL of saturated aqueousammonium chloride, 500 mL of water, and 500 mL of saturated aqueoussodium chloride. The organic layer was separated, dried over magnesiumsulfate, filtered and concentrated under vacuum to afford 180.3 g ofcrude product as an orange solid. The material was used directly in StepH without purification.

¹ H NMR (200 MHz, CDCl₃): δ 1.50 (s, 9H), 1.54 (s, 6H), 2.77 (s, 2H).

Step H:

3-t-Butoxycarbonylamino-3-methylbutanoic acid

A 3 L, 3-neck round bottom flask equipped with a magnetic stirrer,thermometer, nitrogen bubbler and addition funnel was charged with 180.3g (0.89 mol) of N-(t-butoxycarbonyl)-4,4-dimethylazetidin-2-onedissolved in 1 L of tetrahydrofuran. The solution was cooled to 0°-5° C.and treated dropwise with 890 mL of 1.0 M aqueous lithium hydroxide over30 minutes. The reaction mixture was stirred at 0°-5° C. for 2 hours,then diluted with 1 L of ether and 1 L of water. The layers were allowedto separate and the aqueous layer was reextracted with an additional 1 Lof ether. The aqueous layer was acidified by the addition of 1 L ofsaturated aqueous sodium bisulfate, then extracted with 1×1 L and 2×500mL of ether. The combined organic layer and ether extracts were washedwith 500 mL of saturated aqueous sodium chloride, dried over magnesiumsulfate and concentrated under vacuum to give 173 g of a yellow oil thatsolidified upon standing. The material was slurried with warm hexane,then filtered and dried under high vacuum to afford 168.5 g (0.775 mol,87%) of product as a white solid. ¹ H NMR (200 MHz, CDCl₃): δ 1.39 (s,6H), 1.44 (s, 9H), 2.72 (s, 2H). FAB-MS: calculated for C₁₀ H₁₉ NO₄ 217;found 218 (M+H,54%).

Step I:

3-t-Butoxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-butanamide

A solution of 8.70 g (49.4 mmol) of3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step E) in 100 mLof methylene chloride was treated with 10.73 g (49.4 mmol) of3-t-butoxycarbonylamino-3-methylbutanoic acid (Step H) and 13.8 mL oftriethylamine (10.0 g, 99 mmol, 2 eq.). The reaction flask was immersedin an ambient temperature water bath then 26 g ofbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(59 mmol, 1.2 eq) was added all at once and the mixture stirred at roomtemperature for 2 hours. The reaction mixture was added to 300 mL ofethyl acetate and washed three times with 5% aqueous citric acid, twicewith saturated aqueous sodium bicarbonate and once with saturatedaqueous sodium chloride. The organic layer was removed, dried overmagnesium sulfate, filtered and the filtrate concentrated under vacuum.The residue was purified by preparative high pressure liquidchromatography on silica, eluting with ethyl acetateexane (4:1), toafford 17.42 g (46.4 mmol, 94%) of the product as a white solid. ¹ H NMR(200 MHz, CDCl₃): δ 1.37 (s, 6H), 1.44 (s, 9H), 1.95 (m, 1H), 2.46 (d,15 Hz, 1H), 2.59 (d, 15 Hz, 1H), 2.6-3.0, (m, 3H), 4.53 (m, 1H), 5.30(br s, 1H), 6.72 (d, 7 Hz, 1H), 6.98 (d, 8 Hz, 1H), 7.1-7.3 (m, 3H),7.82 (br s, 1H). FAB-MS: calculated for C₂₀ H₂₉ N₃ O₄ 375; found 376(M+H,70%).

Step J:

4-Methyl-2'-nitro-1,1'-biphenyl

A vigorously stirred mixture of 4-tolylboronic acid (34 g, 0.25 mol) and2-bromo-1-nitrobenzene (34 g, 0.168 mol) in a mixture of 5 N sodiumhydroxide (170 mL), water (57 mL), isopropanol (215 mL) and benzene(1080 mL) under a nitrogen atmosphere was treated with(tetrakis)triphenylphosphine palladium (0) (11.9 g). The stirred bilayerreaction mixture was heated at reflux for 3 hours. The cooled reactionmixture was filtered through Celite and the filter cake washed withfresh benzene. The organic layer was separated and washed with water(3×), dried over magnesium sulfate and filtered. The filtrate wasevaporated under vacuum and the residue (46.1 g) purified by preparativehigh pressure liquid chromatography on silica gel, eluting withhexanethyl acetate (20:1) gave 28.05 g of the product. EI-MS: calculatedfor C₁₃ H₁₁ NO₂ 213; found 213 (M⁺). ¹ H NMR (400 MHz, CDCl₃): δ 2.38(s, 3H), 7.20 (m, 4H), 7.43 (m, 2H), 7.59 (t, 1H), 7.8 (d, 1H).

Step K:

4-Bromomethyl-2'-nitro-1,1'-biphenyl

A solution of 4-methyl-2'-nitro-1,1'-biphenyl (Step J) (6.0 g, 28.2mmol), N-bromosuccinimide (4.99 g, 28.2 mmol) and AIBN (653 mg) in 75 mLof carbon tetrachloride was heated at reflux until a negative potassiumiodide test was obtained (1.5 h). The reaction mixture was cooled andfiltered. The filtrate was evaporated under vacuum to yield 8.41 g ofcrude product. ¹ H NMR revealed the product composition was approximatly75% monobromo and 10% dibromo, in addition to 15% of unreacted startingmaterial. ¹ H NMR (200 MHz, CDCl₃): δ 4.53 (s, 2H), 7.2-7.7 (m, 7H),7.85 (m, 1H). EI-MS: calculated for C₁₄ H₁₀ BrN 272; found 272,274 (M⁺).

Step L:

4-Hydroxymethyl-2'-nitro-1,1'-biphenyl

A solution of 4-bromomethyl-2'-nitro-1,1'-biphenyl (7.27 g, 24.8 mmol)in acetic acid (50 mL) was treated with potassium acetate (4.88 g, 49.1mmol). The reaction mixture was heated at reflux for 2 hours. Aftercooling, the reaction mixture was filtered and the precipitate waswashed with acetic acid (2×). The filtrate was evaporated under vacuumand the residue was triturated with ethyl ether. The ether layer waswashed consecutively with water, saturated aqueous sodium bicarbonate(3×) and water. The organic layer was dried over magnesium sulfate,filtered and evaporated under vacuum. The residue was dissolved inmethanol (50 mL) and treated with a 6 N methanolic potassium hydroxidesolution (5 mL). After stirring for 1 hour at room temperature, thinlayer chromatography indicated the absence of starting material. Thereaction mixture was acidified with acetic acid and evaporated undervacuum. The residue was washed free of acetic acid by washing an etheralsolution with aqueous sodium bicarbonate and water. After drying overmagnesium sulfate, the ethereal solution was evaporated under vacuum.The residue was purified by preparative high pressure liquidchromatography on silica gel, eluting with hexanethyl acetate (3:1) togive 2'-nitro-1,1'-biphenyl-4-carboxaldehyde (620 mg) followed by4-hydroxymethyl-2'-nitro-1,1'-biphenyl (3.06 g, 13.4 mmol, 54%).

Step M:

4-(Tetrahydropyranyloxy)methyl-2'-nitro-1,1'-biphenyl

A solution of 4-hydroxymethyl-2'-nitro-1,1'-biphenyl (3.06 g, 13.4 mmol)and 3,4-dihydropyran (1.8 mL, 20.1 mmol) in methylene chloride (50 mL)under a nitrogen atmosphere was treated with pyridiniump-toluenesulfonate (336 mg, 1.34 mmol). After stirring for 3 hours atroom temperature, thin layer chromatography indicated that no startingmaterial remained. The reaction mixture was diluted with ethyl ether(300 mL). The ether extracts were washed with saturated aqueous sodiumchloride, dried over magnesium sulfate and filtered. The filtrate wasevaporated under vacuum and the residue purified by preparative highpressure liquid chromatography on silica gel, eluting with hexane/ethylacetate (10:1) to give 4.47 g of the product.

Step N:

4-(Tetrahydropyranyloxy)methyl-2'-amino-1,1'-biphenyl

A solution of 4-(tetrahydropyranyloxy)methyl-2'-nitro-1,1'-biphenyl(4.12 g, 13.2 mmol) in 100 mL of methanol was hydrogenated at 40 psi inthe presence of 5% palladium on carbon. After 2 hours, uptake ofhydrogen was complete. The reaction mixture was filtered throughdiatomacious earth, and the filter cake washed with methanol. Thefiltrate was evaporated under vacuum to yield 3.57 g of the product.

Step O:

4-Hydroxymethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl

A solution of (tetrahydropyranyloxy)methyl-2-amino-1,1'-biphenyl (500mg, 1.76 mmol) in pyridine (6 mL) was treated with methyl chloroformate(0.41 mL, 5.3 mmol). The reaction mixture was stirred at roomtemperature for 48 hours. The reaction mixture was evaporated undervacuum. The residue was taken up in ethyl ether and washed with water(3×). The ether layer was dried over magnesium sulfate, filtered andevaporated under vacuum to yield 547 mg of crude4-(tetrahydropyranyloxy)methyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl.

The crude4-(tetrahydropyranyloxy)methyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl(250 mg) dissolved in 4 mL of methanol was treated with 1 mL of 10%methanolic p-toluenesulfonic acid. The reaction mixture was stirred atroom temperature for 1 hour. The reaction mixture was made basic by theaddition of saturated aqueous sodium bicarbonate, then diluted withethyl acetate. The organic layer was washed with water (2×), dried overmagnesium sulfate and evaporated under vacuum. The residue was purifiedby preparative thin layer chromatography on silica gel, eluting withmethylene chloride/methanol (100:3) to give 137 mg of the product.FAB-MS (Li⁺ spike): calculated for C₁₅ H₁₅ NO₃ (257); found 264 (M+Li).¹ H NMR (200 MHz,CDCl₃): δ 3.51 (s, 3H), 4.75 (s, 2H), 6.62 (br s, 1H),7.14 (dd, 2H), 7.34 (dd, 1H), 7.4 (dd, 4H).

Step P:

4-Bromomethyl-2-(methoxycarbonyl)amino-1,1'-biphenyl

A solution of 4-hydroxymethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl(239 mg, 0.93 mmol) in methylene chloride (4 mL) was treated withbromotrimethylsilane (3.0 mL, 22.7 mmol). The reaction mixture wasstirred at room temperature for 18 hours. The reaction mixture wasdiluted with additional methylene chloride and washed with saturatedaqueous sodium chloride. After drying over magnesium sulfate, thefiltered organic layer was evaporated under vacuum The residue waspurified by preparative thin layer chromatography on silica gel, elutingwith methylene chloridemethanol (100:3) to give 190 mg of the product.

Step Q:

N- 1- 2'- (Methoxycarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 222 mg (0.594 mmol) of 3-t-butoxycarbonylamino-3-methyl-N- 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!butanamide (Step I)in 6 mL of dry dimethylformamide was treated with 30 mg of 60% sodiumhydride oil dispersion (18 mg NaH, 0.75 mmol, 1.3 eq). The reactionmixture was stirred at room temperature for 30 minutes. To the solutionwas added 190 mg (0.594 mmol) of solid4-bromomethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl. After stirring atroom temperature for 1 hour, the reaction mixture was diluted with ethylacetate followed by 50 mL of water. The organic layer was washed withwater (4×), dried over magnesium sulfate, filtered and evaporated undervacuum. The residue was purified by preparative thin layerchromatography on silica gel, eluting with methylene chlorideethanol(100:3) to give 231 mg (0.376 mmol, 63%) of the product. ¹ H NMR (400MHz, CDCl₃): δ 1.23 (s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 1.85 (m, 1H),2.40 (dd, 2H), 2.49 (m, 1H), 2.54 (m, 2H), 3.68 (s, 3H), 4.53 (m, 1H),4.94 (d, 1H), 5.17 (d, 1H), 6.53 (br s, 1H), 6.66 (d, 1H), 7.2 (m, 12H),8.09 (d, 1H).

Step R:

N- 1- 2'- (Methoxycarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 86 mg (0.14 mmol) of the intermediate obtained in Step Qin 2 mL of methylene chloride was treated with 1.0 mL of trifluoroaceticacid. After stirring at room temperature for 1 hour, all volatiles wereremoved under vacuum and the residue purified by medium pressure liquidchromatography on C8, eluting with methanolB 0.1% aqueoustrifluoroacetic acid (60:40). The fractions containing the product werecombined and solvents removed under vacuum. The residue was lyophilizedfrom water to give 69 mg (0.13 mmol, 96%) of the title compound as awhite solid. FAB-MS: calculated for C₃₀ H₃₄ N₄ O₄ 514; found 515 (M+H).¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s, 3H), 1.39 (s, 3H), 2.12 (m, 1H),2.31 (m, 1H), 2.52 (dd, 2H), 2.6 (m, 2H), 3.54 (br s, 3H), 4.40 (dd,1H), 5.02 (d, 1H), 5.28 (d, 1H), 7.30 (m, 12H), 7.54 (br s, 1H).

EXAMPLE 2 N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- (2'-Nitro)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!amino-3-methylbutanamide

Prepared from 4-bromomethyl-2'-nitro-1,1'-biphenyl (Example 1, Step K)and 3-t-butoxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-butanamide (Example 1,Step I) by the procedure described in Example 1, Step Q. ¹ H NMR (400MHz, CDCl₃): δ 1.34 (s, 6H), 1.41 (s, 9H), 1.83 (m, 1H), 2.35-2.70 (m,5H), 4.50 (m, 1H), 4.84 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 5.27 (s,1H), 6.64 (d, 7 Hz, 1H), 7.1-7.6 (m, 11H), 7.80 (d, 8 Hz, 1H). FAB-MS:calculated for C₃₃ H₃₈ N₄ O₆ 586; found 587 (M+H).

Step B:

N- 1- (2'-Amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 7.79 g (13.23 mmol) of the intermediate obtained in Step Ain 200 mL of methanol containing 0.9 g of 5% palladium on carbon washydrogenated at 40 psi. When the uptake of hydrogen was complete, thecatalyst was removed by filtration through Celite. The filtrate wasconcentrated under vacuum to yield 6.6 g (11.9 mmol, 90%) of product.FAB-MS: calculated for C₃₃ H₄ N₄ O₄ 556; found 557(M+H). ¹ H NMR (400MHz, CDCl₃): δ 1.32 (s, 6H), 1.39 (s, 9H), 1.87 (m, 1H), 2.51 (dd, 1H),2.59 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.15 (d, 1H), 5.32 (br s, 1H),6.71 (d, 1H), 6.81 (s, 1H), 7.21 (m, 10H).

Step C:

N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 88.4 mg (0.158 mmol) of the intermediate obtained in StepB in 4 mL of methylene chloride at room temperature was treated with 0.5mL of methyl isocyanate (8.5 mmol). The reaction mixture was stirred atroom temperature for 18 hours, when all starting material was consumedas indicated by thin layer chromatography. The reaction was evaporatedunder vacuum and the residue passed over silica gel. Elution with ethylacetate-hexane (3:1) yielded 66 mg (0.11 mmol,68%) of product. ¹ H NMR(400 MHz, CDCl₃): δ 1.21 (s, 3H), 1.23 (s, 3H), 1.39 (s, 9H), 1.89 (m,1H), 2.49 (dd, H), 2.60 (m, 2H), 2.69 (s, 3H), 4.50 (m, 1H), 4.95 (d,1H), 5.06 (d, 1H), 5.26 (br s, 1H), 6.24 (br s, 1H), 6.70 (d, 1H), 7.22(m, 11H), 7.71 (d, 1H).

Step D:

N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 66 mg (0.11 mmol) of the intermediate obtained in step Cin 2 mL of methylene chloride was treated with 2 mL of trifluoroaceticacid. The reaction mixture was stirred at room temperature for 1 hour,when thin layer chromatography indicated that no starting materialremained. The reaction mixture was evaporated to dryness under vacuumand the residue purified by medium pressure liquid chromatography on C8,eluting with methanolB 0.1% aqueous trifluoroacetic acid (60:40).Fractions containing the product were combined and evaporated undervacuum and the residue lyophilized from water to give 26 mg (0.051mmol,46%) of the title compound as a white solid. FAB-MS: calculated forC₃₀ H₃₅ N₅ O₃ 513; found 536 (M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ 1.34(s, 3H), 1.37 (s, 3H), 2.13 (m, 1H), 2.39 (m, 1H), 2.54 (dd, 1H), 2.63(s, 3H), 3.29 (dd, 1H), 4.95 (d, 1H), 5.11 (d, 1H), 7.22 (m, 10H), 7.60(d, 1H).

EXAMPLE 3 N- 1- 2'- (Ethylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluroroacetate

Step A:

N- 1- 2'- (Ethylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from N- 1- (2'-amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 2, Step B) and ethyl isocyanate by the procedure described inExample 2, Step C.

Step B:

N- 1- 2'- (Ethylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from the intermediate obtained in Step Aby the procedure described in Example 2, Step D. FAB-MS: calculated forC₃₁ H₃₇ N₅ O₃ 527; found 550(M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ 1.04(t, 3H), 1.34 (s, 3H), 1.38 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.52(dd, 2H), 2.62 (m, 2H), 3.09 (q, 2H), 4.41 (dd, 1H), 5.01 (d, 1H), 5.24(d, 1H), 7.24 (m, 11H), 7.60 (d, 1H).

EXAMPLE 4 N- 1- 2'- (2-Propylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- 2'- (2-Propylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from N- 1- (2'-amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 2, Step B) and isopropyl isocyanate by the procedure describedin Example 2, Step C. ¹ H NMR (400 MHz, CDCl₃): δ 1.06 (d, 3H) 1.07 (d,3H), 1.32 (s, 3H), 1.39 (s, 9H), 1.88 (m, 1H), 2.48 (dd, 1H), 2.50 (m,1H), 2.62 (m, 2H), 3.80 (m, 1H), 4.52 (m, 1H), 4.98 (d, 1H), 5.10 (d,1H), 5.28 (br s, 1H), 6.08 (br s, 1H), 6.68 (br s, 1H), 7.22 (m, 11H),7.70 (d, 1H).

Step B:

N- 1- 2'- (2-Propylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from the intermediate obtained in Step Aby the procedure described in Example 2, Step D. FAB-MS: calculated forC₃₂ H₃₉ N₅ O₃ 541; found 541(M⁺). ¹ H NMR (400 MHz, CD₃ OD): δ 1.05 (dd,6H), 1.34 (s, 3H), 1.37 (s, 3H), 2.5 (m, 1H), 2.34 (m, 1H), 2.5 (m, 1H),2.64 (m, 2H), 3.73 (m, 1H), 4.41 (dd, 1H), 5.02 (d, 1H), 5.24 (d, 1H),7.3 (m, 12H), 7.63 (d, 1H).

EXAMPLE 5 N- 1- 2'- (Aminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- 2'- (Aminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 445 mg (0.80 mmol) of N- 1- (2'-amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 2, Step B) in 3 mL of methylene chloride under a nitrogenatmosphere was treated with 4 mL (29.5 mmol) of trimethylsilylisocyanate. The reaction mixture was stirred at room temperature for 18hours. The reaction mixture was evaporated under vacuum and the residuewas passed over silica gel. Elution with ethyl acetateexanes (4:1)yielded 211 mg (0.35 mmol, 44%) of product. FAB-MS: calculated for C₃₄H₄₁ N₅ O₅ 599: found 622 (M+Na). ¹ H NMR (400 MHz, CDCl₃): δ 1.31 (s,3H), 1.38 (s, 3H), 1.39 (s, 9H), 1.90 (m, 1H), 2.48 (dd, 2H), 2.60 (m,2H), 4.48 (m, 1H), 4.95 (d, 1H), 5.08 (d, 1H), 5.28 (br s, 1H), 6.66 (brs, 1H), 6.78 (d, 1H), 7.22 (m, 11H), 7.72 (d, 1H).

Step B:

N- 1- 2'- (Aminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from the intermediate obtained in Step Aby the procedure described in Example 2, Step D. FAB-MS: calculated forC₂₉ H₃₃ N₅ O₃ 499; found 500(M+H). ¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s,3H), 1.37 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.50 (dd, 1H), 2.65 (m,2H), 4.42 (dd, 1H), 5.02 (d, 1H), 5.25 (d, 1H), 7.27 (m, 10, H), 7.60(d, 1H).

EXAMPLE 6 N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- (2'-Isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 2.0 g (3.6 mmol) of N- 1- (2'-amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 2, Step B) and 2.0 mL of triethylamine (14 mmol) in 40 mL ofmethylene chloride under a nitrogen atmosphere was cooled to -10° C. andtreated with 2.12 g (7.15 mmol) of triphosgene in one portion. Anexotherm occurred. The reaction was stirred at room temperature for 1.5hours when no starting amine was detected by thin layer chromatographyon silica (hexanethyl acetate (1:1)). The reaction mixture was dilutedwith 40 mL of hexane and filtered. The filtrate was passed over 150 g ofsilica gel and eluted with hexane/ethyl acetate (1:1) to give 1.65 g(2.84 mmol, 79%) of the product. ¹ H NMR (400 MHz, CDCl₃): δ 1.34 (s,6H), 1.39 (s, 9H), 1.84 ((m, 1H), 2.40 (m, 1H), 2.49 (dd, 1H), 2.52 (m,1H), 4.51 (m, 1H), 4.88 (d, 1H), 5.25 (d, 1H), 5.34 (br s, 1H), 6.71 (d,1H), 7.20 (m, 12H).

Step B:

N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 100 mg (0.17 mmol) of the intermediate obtained in Step Ain 2 mL of methylene chloride was treated with 0.017 mL of morpholine(0.19 mmol). The reaction mixture was stirred at room temperature for 1hour when thin layer chromatography showed no remaining isocyanate. Tothe reaction mixture was added 1 mL of trifluoroacetic acid. Thereaction mixture was stirred at room temperature for 0.5 hours. Thereaction mixture was evaporated under vacuum and the residue purified bypreparative medium pressure reverse phase liquid chromatography on C8,eluting with methanol/0.1% aqueous trifluoroacetic acid (65:35). Thefractions containing the product were combined and evaporated undervacuum and the residue was lyophilized from water to afford 88 mg (0.15mmol, 88%) of the title compound as a white solid. FAB-MS: calculatedfor C₃₃ H₃₉ N₅ O₄ 569; found 592 (M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ1.35 (s, 3H), 1.39 (s, 3H), 2.12 (m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H),2.60 (m, 2H), 3.25 (m, 4H), 3.54 (m, 4H), 4.40 (dd, 1H), 4.95 (d, 1H),5.30 (d, 1H), 7.3 (m, 12H).

EXAMPLE 7 N- 1- 2'- (Piperazinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand piperazine by the methods described in Example 6. FAB-MS: calculatedfor C₃₃ H₄₀ N₆ O₃ 568; found 593 (M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ1.27 (s, 3H), 1.30 (s, 3H), 2.07 (m, 1H), 2.30 (m, 1H), 2.4 (dd, 2H),2.59 (m, 2H), 3.20 (dd, 4H), 3.30 (dd, 4H), 4.40 (dd, 1H), 4.90 (d, 1H),5.33 (d, 1H), 7.30 (m, 12H).

EXAMPLE 8 N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand ethanolamine by the procedure described in Example 6, Step A.FAB-MS: calculated for C₃₆ H₄₅ N₅ O₆ 643; found 666 (M+Na). ¹ H NMR (400MHz, CDCl₃): δ 1.29 (s, 3H), 1.31 (s, 3H), 1.38 (s, 9H), 1.90 (m, 1H),2.5 (dd, 2H), 2.58 (m, 2H), 2.7 (m, 1H), 3.21 (t, 2H), 3.54 (m, 2H),4.49 (m, 1H), 4.88 (d, 1H), 5.10 (d, 1H), 6.81 (d, 1H), 7.21 (m, 11H),7.74 (d, 1H).

Step B:

N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from the intermediate obtained in Step Aby the procedure described in Example 6, Step B. FAB-MS: calculated forC₃₁ H₃₇ N₅ O₄ 543: found 545. ¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s, 3H),1.37 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.52 (dd, 2H), 2.64 (m, 2H),3.20 (t, 2H), 3.51 (t, 2H), 4.41 (dd, 1H), 5.02 (d, 1H), 5.20 (d, 1H),7.24 (m, 11H), 7.62 (d, 1H).

EXAMPLE 9 N- 1- 2'- (2-Hydroxypropylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand 1-amino-2-propanol by the procedures described in Example 6. FAB-MS:calculated for C₃₂ H₃₉ N₅ O₄ 557; found 580 (M+Na). ¹ H NMR (400 MHz,CD₃ OD): δ 1.00 (d, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 2.14 (m, 1H), 2.34(m, 1H), 2.52 (dd, 2H), 2.68 (m, 2H), 3.01 (dd, 1H), 4.41 (dd, 1H), 5.02(d, 1H), 5.21 (d, 1H), 7.25 (m, 11H), 7.62 (d, 1H).

EXAMPLE 10 N- 1- 2'- (3-Hydroxypropylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand 3-amino-1-propanol by the procedures described in Example 6. FAB-MS:calculated for C₃₂ H₃₉ N₅ O₄ 557; found 580 (M+Na). ¹ H NMR (400 MHz,CD₃ OD): δ 1.34 (s, 3H), 1.38 (s, 3H), 1.60 (m, 2H), 2.18 (m, 1H), 2.35(m, 1H), 2.52 (dd, 2H), 2.65 (m, 3H), 3.39 (m, 2H), 3.52 (m, 2H), 4.42(dd, 1H), 5.04 (d, 1H), 5.21 (d, 1H), 7.28 (m, 11H), 7.59 (d, 1H).

EXAMPLE 11 N- 1- 2'- (2,3-Dihydroxypropylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand 3-amino-1,2-propanediol by the procedures described in Example 6.FAB-MS: calculated for C₃₂ H₃₉ N₅ O₄ 557; found 580(M+Na). ¹ H NMR (400MHz, CD₃ OD): δ 1.34 (s, 3H), 1.37 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H),2.51 (dd, 1H), 2.66 (m, 2H), 3.09 (m, 1H), 3.2 (m, 2H), 3.42 (m, 2H),3.59 (m, 1H), 4.41 (dd, 1H), 5.05 (d, 1H), 5.17 (d, 1H), 7.25, (m, 10H),7.59 (d, 1H).

EXAMPLE 12 N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

4-Methylphenyltrimethylstannane

41.4 L of 1.0 M p-tolylmagnesium bromide in diethyl ether (41.4 mol) wasadded dropwise, maintaining the temperature below -5° C., over 4 hoursto a solution of 546 g (2.79 mol) of trimethyltin chloride intetrahydrofuran (4 L) under nitrogen at -10° C. The suspension wasallowed to warm slowly to room temperature over 12 hours then saturatedammonium chloride solution (1 L) was added followed by sufficient water(approximately 1 L) to dissolve the precipitate. The solution wasextracted with ether-hexane (1:1) (1×4 L, 3×2 L). The combined organicphases were washed with brine, dried over magnesium sulfate and thesolvents removed under vacuum. Purification by flash chromatography onsilica gel eluting with hexanethyl acetate (95:5) gave a pale yellow oilcontaining white crystals of 4,4'-dimethylbiphenyl which were removed byfiltration to leave 711.3 g (100%) of product. ¹ H NMR (300 MHz, CDCl₃):δ 0.30 (s, 9H), 2.34 (s, 3H), 7.19 (d, 7.7 Hz, 2H), 7.40 (d, 7.7 Hz,2H).

Step B:

4-Methyl-2'-acetyl-1,1'-biphenyl

A vigorously stirred solution of 13.25 g (66 mmol) of2'-bromoacetophenone and 22.8 g (89 mmol) of4-methylphenyltrimethylstannane in 190 mL of dimethylformamide under anitrogen atmosphere was treated with 8.64 g (12 mmol) ofbis(triphenylphosphine)palladium(II) chloride and the resulting mixtureheated at 150° C. for 6 hours. The reaction mixture was cooled, pouredinto water (1000 mL) and the resultant suspension extracted with ethylether. The combined extracts were washed with water (4×), dried overmagnesium sulfate and evaporated under vacuum. The residue was purifiedby preparative high pressure liquid chromatography on silica gel,eluting with hexane/ethyl acetate (10:1) to give 9.8 g (47 mmol, 71%) ofproduct as an oil. EI-MS: calculated for C₁₅ H₁₄ O 210: found 210 (M⁺).¹ H NMR (200 MHz, CDCl₃): δ 1.98 (s, 3H), 2.37 (s, 3H), 7.20 (s, 4H),7.3-7.5 (m, 4H).

Step C:

4-Methyl-2'-hydroxy-1,1'-biphenyl

A solution of 4.2 g (20.0 mmol) of 4-methyl-2'-acetyl-1-1'-biphenyl(Step B) in methylene chloride under a nitrogen atmosphere was treatedwith 8.98 g of 85% m-chloroperbenzoic acid. The resultant suspension wascooled to 0° C. and treated dropwise with 1.54 mL of trifluoroaceticacid over a 10 minute period. The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was diluted with 50 mL ofmethylene chloride and the solution was washed successively with 50 mLof 10% sodium sulfite, 50 mL of saturated aqueous potassium carbonateand water (3×50 mL). The organic layer was removed and dried overmagnesium sulfate, then evaporated under vacuum to yield 4.1 g of anoil. The oil was dissolved in 20 mL of methanol and treated with 2.0 mLof 5N aqueous sodium hydroxide. The reaction mixture was stirred at roomtemperature for 1 hour. The pH of the solution was adjusted to 5-6 withacetic acid. After the methanol was removed under vacuum, the residuewas taken up in ether, washed with water, dried over magnesium sulfate,filtered and evaporated under vacuum to yield 3.0 g of crude productwhich was purified by preparative high pressure liquid chromatography onsilica, eluting with hexane/ethyl acetate (10:1). In this manner, 1.85 g(10.0 mmol, 50%) of the product was obtained as an oil. ¹ H NMR (200MHz, CDCl₃): δ 2.40 (s, 3H), 5.22 (br s, 1H), 6.96 (m, 2H), 7.2-7.4 (m,6H). EI-MS: calculated for C₁₃ H₁₂ O 184; found 184 (M⁺, 100%).

Step D:

4-Methyl-2'-acetoxy-1,1'-biphenyl

A solution of 1.0 g (5.4 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl in2.0 mL of pyridine was treated with 2 mL of acetic anhydride. Thereaction mixture was stirred at room temperature for 5 hours. Thesolvent was removed under vacuum to yield 1.11 g (4.9 mmol, 90%) of theproduct as an oil. ¹ H NMR (200 MHz, CDCl₃): δ 2.07 (s, 3H), 2.36 (s,3H), 7.07 (dd; 3, 8 Hz; 1H), 7.15 (d, 8 Hz, 2H), 7.2-7.4 (m, 5H).

Step E:

4'-Bromomethyl-2-acetoxy-1,1'-biphenyl

Prepared from 4-methyl-2'-acetoxy-1,1'-biphenyl by the proceduredescribed in Example 1, Step K. ¹ H NMR (200 MHz, CDCl₃): δ 2.05 (s,3H), 4.50 (s, 2H), 7.08 (m, 1H), 7.20-7.45 (m, 7H).

Step E:

N- 1- (2'-Acetoxy)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from 4-bromomethyl-2'-acetoxy-1,1'-biphenyl and3-t-butoxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-butanamide (Example 1,Step I) by the procedure described in Example 1, Step Q. ¹ H NMR (200MHz, CDCl₃): δ 1.38 (s, 6H), 1.45 (s, 9H), 1.85 (m, 1H), 2.02 (s, 3H),2.35-2.65 (m, 5H), 4.52 (m, 1H), 4.84 (d, 15 Hz, 1H), 5.30 (d, 15 Hz,1H), 6.71 (d, 7 Hz, 1H), 7.1-7.4 (m, 12H).

Step G:

N- 1- (2'-Hydroxy)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 469 mg (0.87 mmol) of the intermediate obtained in Step Fin 25 mL of methanol at room temperature was treated with 5 mL ofaqueous 5N sodium hydroxide. After stirring at room temperature for 1hour, the reaction mixture was evaporated under vacuum and the residuedissolved in methylene chloride, dried over magnesium sulfate andfiltered. The filtrate was evaporated under vacuum to yield 450 mg ofcrude product which was used in the next step without purification.

Step H:

N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 100 mg (approx. 0.2 mmol) of the crude intermediateobtained in Step G in 5 mL of methylene chloride was treated with 1.0 mLof methyl isocyanate (17 mmol) and 0.1 mL of 1,8-diazabicyclo5.4.0!undec-7-ene under a nitrogen atmosphere. The reaction mixture wasstirred at room temperature for 10 minutes and then evaporated undervacuum to give 146 mg of crude product. ¹ H NMR (400 MHz, CDCl₃): δ 1.32(s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52(dd, 1H), 2.57 (m, 2H), 2.59 (s, 3H), 4.38 (dd, 1H), 4.8 (d, 1H), 5.26(d, 1H), 7.10 (d, 1H), 7.36 (m, 11H).

Step I:

N- 1- 2'- (Methylaminocarbonyl)oxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 72 mg of the crude intermediate obtained in Step H in 3.5mL of methylene chloride was treated with 1.0 mL of trifluoroaceticacid. After stirring at room temperature for 15 minutes, the reactionmixture was evaporated under vacuum and the residue purified by reversephase medium pressure liquid chromatography on C8, eluting withmethanolB 0.1% aqueous trifluoroacetic acid (60:40). Fractionscontaining the product were combined, solvents removed under vacuum andthe residue lyophilized from water to give 34 mg (0.066 mmol) of thetitle compound as a white solid. FAB-MS: calculated for C₃₀ H₃₄ N₄ O₄514; found 537 (M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s, 3H), 1.38(s, 3H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52 (dd, 1H), 2.57 (m, 2H), 2.59(s, 3H), 4.38 (dd, 1H), 4.8 (d, 1H), 5.26 (d, 1H), 7.10 (d, 1H), 7.36(m, 11H).

EXAMPLE 13 N- 1- 2'- (Methylaminothiocarbonyl)amino!1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- (2'-Isothiocyanato)1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide,and N- 1- 2'- (methylaminothiocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 300 mg (0.60 mmol) of N- 1- (2'-amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 2, Step B) and 1.8 g of methyl isothiocyanate (25 mmol) in 15mL of benzene under a nitrogen atmosphere was heated at reflux for 24hours. The reaction mixture was evaporated under vacuum and the residuepurified by preparative thin layer chromatography on silica gel, elutingwith ethyl acetateexane (3:1 ) to give 69 mg of a faster moving productidentified as N- 1- (2'-isothiocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide.FAB-MS: calculated for C₃₄ H₃₈ N₄ O₄ S 598; found 621 (M+Na). ¹ H NMR(400 MHz, CDCl₃): δ 1.35 (s, 3H), 1.36 (s, 3H), 1.40 (s, 9H), 1.84 (m,1H), 2.48 (dd, 2H), 2.52 (m, 3H), 4.50 (m, 1H), 4.86 (d, 1H), 5.29 (d,1H), 6.68 (d, 1H), 7.14 (m, 1H), 7.30 (M, 11H).

The slower moving band yielded 122 mg of material identified as N- 1-2'- (methylaminothiocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide.FAB-MS: calculated for C₃₅ H₄₃ N₅ O₄ S 629: found 652 (M+Na). ¹ H NMR(400 MHz, CDCl₃): δ 1.32 (s, 3H), 1.33 (s, 3H), 1.40 (s, 9H), 1.85 (m,1H), 2.48 (dd, 2H), 2.55 (m, 3H), 2.95 (s, 3H), 4.50 (m, 1H), 4.88 (s,1H), 5.20 (s, 1H), 6.68 (d, 1H), 7.22 (m, 12H).

Step B:

N- 1- 2'- (Methylaminothiocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 122 mg (0.19 mmol) of N- 1- 2'-(methylaminothiocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamidein 3 mL of methylene chloride was treated with 1.0 mL of trifluoroaceticacid. After 1 hour thin layer chromatography indicated that no startingmaterial was present. Solvents were removed under vacuum and the residuepurified by reverse phase medium pressure liquid chromatography on C8,eluting with methanolB 0.1% aqueous trifluoroacetic acid (60:40). Thefractions containing the product were combined, solvents evaporatedunder vacuum and the residue was lyophilized from water to give 84 mg(0.16 mmol, 84%) of the title compound as a white solid. FAB-MS:calculated for C₃₀ H₃₅ N₄ O₂ 529; found 531. ¹ H NMR (400 MHz, CD₃ OD):δ 1.32 (s, 3H), 1.38 (s, 3H), 2.11 (m, 1H), 2.30 (m, 1H), 2.53 (dd, 2H),2.70 (m, 2H), 2.72 (s, 3H), 4.4 (dd, 1H), 4.89 (d, 1H), 5.81 (d, 1H),7.3 (m, 12H).

EXAMPLE 14 N- 1- 2'- (Aminothiocarbonyl)amino!1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 100 mg (0.17 mmol) of N- 1- (2'-isothiocyanato)1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 13, Step A) in 5 mL of methanol was treated with gaseousanhydrous ammonia for 5 minutes. Thin layer chromatography revealed nostarting isothiocyanate was present. The reaction mixture was evaporatedunder vacuum and the residue was dissolved in 3 mL of methylene chlorideand treated with 1 mL of trifluoroacetic acid. After 1 hour at roomtemperature the reaction mixture was evaporated under vacuum and theresidue purified by reverse phase medium pressure liquid chromatographyon C8, eluting with methanolB 0.1% aqueous trifluoroacetic acid (60:40).Fractions containing the product were combined, solvents removed undervacuum and the residue lyophilized from water to give 53 mg of the titlecompound as a white solid. FAB-MS: calculated for C₂₉ H₃₃ N₅ O₂ S 515;found 516 (M+H). ¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s, 3H), 1.38 (s,3H), 2.12 (m, 1H), 2.30 (m, 1H), 2.54 (dd, 2H), 2.60 (m, 2H), 4.42 (dd,1H), 4.92 (d, 1H), 5.26 (d, 1H), 7.30 (m, 12H).

EXAMPLE 15 N- 1- 2'- (Dimethylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

4-(Tetrahydropyranyloxy)methyl-2'-isocyanato-1,1'-biphenyl

A solution of 200 mg (0.70 mmol) of4-(tetrahydropyranyloxy)methyl-2'-amino-1,1'-biphenyl (Example 1, StepN) and 0.40 mL of triethylamine in 10 mL of methylene chloride under anitrogen atmosphere was treated with triphosgene (420 mg, 0.24 mmol).The reaction mixture was stirred at room temperature for 30 minutes whenthin layer chromatography on silica (hexanethyl acetate; 2:1) revealedno remaining amine. The reaction mixture was evaporated under vacuum toyield the crude product which was used in the next step withoutpurification.

Step B:

4-Hydroxymethyl-2'-(dimethylaminocarbonyl)amino-1,1'-biphenyl

A solution of the crude intermediate from Step A in 4 mL of methanol wastreated with 4 mL of 40% aqueous dimethylamine. After stirring at roomtemperature for 15 minutes, the reaction mixture was evaporated undervacuum and the residue dissolved in 4 mL of methanol and treated with 1mL of 10% methanolic p-toluenesulfonic acid. After 15 minutes at roomtemperature, the reaction mixture was treated with saturated aqueoussodium bicarbonate. The mixture was diluted with water then extractedwith methylene chloride. The organic layer was dried and evaporatedunder vacuum; the residue was purified by preparative thin layerchromatography on silica gel, eluting with hexane/ethyl acetate (2:1) toafford 133 mg of product.

Step C:

4-Bromomethyl-2'-(dimethylaminocarbonyl)amino-1,1'-biphenyl

A solution of the intermediate obtained in Step B in 4 mL of methylenechloride was treated with 0.16 mL (1.21 mmol) of trimethylsilylbromide.The reaction mixture was stirred at room temperature for 18 hours. Thereaction mixture was diluted with methylene chloride then washed withaqueous saturated sodium chloride (2×). The organic layer was dried overmagnesium sulfate, filtered and evaporated under vacuum to yield 133 mgof crude product. ¹ H NMR (400 Hz, CDCl₃): δ 2.78 (s, 6H), 4.5 (s, 2H),6.4 (br s, 1H), 7.08 (t, 1H), 7.16 (dd, 1H), 7.34 (m, 4H), 7.49 (d, 1H),8.10 (d, 1H).

Step D:

N- 1- 2'- (Dimethylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 147 mg (0.39 mmol) of 3-t-butoxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!butanamide (Example 1,Step I) in 5 mL of dry dimethylformamide was treated with 20 mg of 60%sodium hydrideil dispersion (12 mg NaH,0.5 mmol, 1.3 eq.). The reactionmixture was stirred at room temperature for 30 minutes then 133 mg of4-bromomethyl-2'-(dimethylaminocarbonyl)amino-1,1'-biphenyl was added.After stirring at room temperature for 2 hours, the reaction mixture wasdiluted with ethyl acetate. The mixture was washed with water (4×) andthe organic layer dried over magnesium sulfate, filtered and evaporatedunder vacuum. The residue was dissolved in 4 mL of methylene chlorideand treated with 1 mL of trifluoroacetic acid. After stirring at roomtemperature for 1.5 hours, solvents were removed under vacuum and theresidue purified by reverse phase medium pressure liquid chromatographyon C8, eluting with methanol/0.1% aqueous trifluoroacetic acid (65:35).Fractions containing the product were combined, solvents removed undervacuum and the residue lyophilized from water to give 116 mg of thetitle compound as a white solid. FAB-MS: calculated for C₃₁ H₃₇ N₅ O₃527; found 529. ¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s, 3H), 1.40 (s, 3H),2.15 (m, 1H), 2.34 (m, 1H), 2.54 (dd, 2H), 2.59 (m, 2H), 2.78 (s, 6H),4.44 (dd, 1H), 4.88 (d, 1H), 5.38 (d, 1H), 7.28 (m, 11H), 7.49 (d, 1H).

EXAMPLE 16 N- 1- 2'- (1,3-Dihydroxyprop-2-yl)aminocarbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- 2'- (1,3-Dihydroxyprop-2-yl)aminocarbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 125 mg (0.23 mmol) of N- 1- (2'-amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 2, Step B) and 0.10 mL (0.72 mmol) of triethylamine in 5 mL ofmethylene chloride under a nitrogen atmosphere was cooled to -10° C. andtreated with 133 mg (0.45 mmol) of triphosgene. The reaction mixture wasallowed to warm to room temperature and stirred for 1 hour. The reactionmixture was recooled to -10° C. and additional triethyl amine (0.30 mL,0.23 mmol) was added. The reaction mixture was treated with serinolhydrochloride (280 mg, 2.20 mmol) in one portion. The reaction mixturewas stirred at room temperature when thin layer chromatography(hexanethyl acetate: 1:1) indicated no remaining isocyanate. Thereaction mixture was evaporated under vacuum to give the crude product.

Step B:

N- 1- 2'- (1,3-Dihydroxyprop-2-yl)aminocarbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of the crude intermediate obtained in Step A in 5 mL ofmethylene chloride was treated with 2 mL of trifluoroacetic acid. Afterstirring at room temperature for 1 hour, the reaction mixture wasevaporated under vacuum and the residue purified by reverse phase mediumpressure liquid chromatography on C8, eluting with methanolB 0.1%aqueous trifluoroacetic acid (55:45). Fractions containing the productwere combined, solvents removed under vacuum and the residue lyophilizedfrom water to give 66 mg (0.096 mmol, 42% over two steps) of the titlecompound as a white solid. FAB-MS: calculated for C₃₂ H₃₉ N₅ O₅ 573;found 596 (M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s, 3H), 1.37 (s,3H), 2.14 (m, 1H), 2.30 (m, 1H), 2.48 (dd, 2H), 2.69 (m, 2H), 3.52 (m,4H), 3.70 (m, 1H), 4.40 (dd, 1H), 5.05 (d, 1H), 5.20 (d, 1H), 7.25 (m,11H), 7.62 (d, 1H).

EXAMPLE 17 N- 1- 2'- 2(R)-Hydroxypropylamino!carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand (R)-(-)-1-amino-2-propanol by the methods described in Example 6.FAB-MS: calculated for C₃₂ H₃₉ N₅ O₄ 557; found 580 (M+Na). ¹ H NMR (400MHz, CD₃ OD): δ 1.09 (d, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 2.15 (m, 1H),2.35 (m, 1H), 2.52 (dd, 2H), 2.65 (m, 2H), 2.95 (dd, 1H), 3.16 (dd, 1H),3.75 (m, 1H), 4.82 (dd, 1H), 5.02 (d, 1H), 5.20 (d, 1H), 7.27 (m, 11H),7.61 (d, 1H).

EXAMPLE 18 N- 1- 2'- 2(S)-Hydroxypropylamino!carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand (S)-(+)-1-amino-2-propanol by the methods described in Example 6.FAB-MS: calculated for C₃₂ H₃₉ N₅ O₄ 557; found 581 (M+Na). ¹ H NMR (400MHz, CD₃ OD): δ 1.09 (d, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 2.15 (m, 1H),2.45 (m, 1H), 2.55 (dd, 2H), 2.68 (m, 2H), 3.02 (dd, 1H), 3.16 (dd, 1H),3.75 (m, 1H), 4.41 (dd, 1H), 5.06 (d, 1H), 5.22 (d, 1H), 7.27 (m, 11H),7.62 (d, 1H).

EXAMPLE 19 N- 1- 2'- 1-Hydroxyprop-2(R)-yl!amino!carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand (R)-2-amino-1-propanol by the methods described in Example 6.FAB-MS: calculated for C₃₂ H₃₉ N₅ O₄ 557; found 580 (M+Na). ¹ H NMR (400MHz, CD₃ OD): δ 1.07 (d, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 2.15 (m, 1H),2.35 (m, 1H), 2.51 (dd, 2H), 3.41 (m, 2H), 3.75 (m, 1H), 4.41 (dd, 1H),5.03 (d, 1H), 5.21 (d, 1H), 7.25 (m, 11H), 7.64 (d, 1H).

EXAMPLE 20 N- 1- 2'- (Hydrazinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand anhydrous hydrazine by the methods described in Example 6. FAB-MS:calculated for C₂₉ H₃₅ N₆ O₃ 514: found 537 (M+Na). ¹ H NMR (400 MHz,CD₃ OD): δ 1.35 (s, 3H), 1.38 (s, 3H), 2.29 (m, 1H), 2.35 (m, 1H), 2.57(dd, 1H), 2.62 (m, 2H), 4.46 (dd, 1H), 5.30 (d, 1H), 7.29 (m, 10H), 7.73(d, 1H).

EXAMPLE 21 N- 1- 2'- (2,2-Dimethylhydrazinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand 1,1-dimethylhydrazine by the methods described in Example 6. FAB-MS:calculated for C₃₁ H₃₈ N₆ O₃ 542; found 565 (M+Na). ¹ H NMR (400 MHz,CD₃ OD): δ 1.34 (s, 3H), 1.38 (s, 3H), 2.14 (m, 1H), 2.30 (s, 6H), 2.36(m, 1H), 2.52 (dd, 1H), 2.64 (m, 2H), 4.28 (dd, 1H), 5.00 (dd, 1H), 5.30(dd, 1H), 7.26 (m, 10H), 7.90 (d, 1H).

EXAMPLE 22 N- 1- 2'- (Carboxymethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

N- 1- 2'- (t-Butoxycarbonylmethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from N- 1- (2'-amino)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide(Example 2, Step B) and glycine t-butyl ester hydrochloride by theprocedure described in Example 16, Step A.

Step B:

N- 1- 2'- (Carboxymethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate, and N- 1- 2'-(Methoxycarbonylmethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of the crude intermediate obtained in Step A in 4 mL ofmethylene chloride was treated with 2 mL of trifluoroacetic acid. Afterstirring at room temperature for 1 hour, the reaction mixture wasevaporated under vacuum and the residue purified by reverse phase mediumpressure liquid chromatography on C8, eluting with methanolB 0.1%aqueous trifluoroacetic acid (55:45). The early fractions containing theproduct were combined, solvents removed under vacuum and the residue waslyophilized from water to give 60 mg of the title compound as a whitesolid. FAB-MS: calculated for C₃₁ H₃₅ N₅ O₅ 557: found 558 (M+H). ¹ HNMR (400 MHz, CD₃ OD:) δ 1.34 (s, 3H), 1.38 (s, 3H), 2.15 (m, 1H), 2.34(m, 1H), 2.52 (dd, 2H 2.68 (m, 2H), 3.84 (s, 2H), 4.42 (s, 1H), 5.05 (d,1H), 5.20 (d, 1H), 7.25 (m, 11H), 7.64 (d, 1H).

Later fractions were combined, solvents removed under vacuum and theresidue lyophilized from water to give 18 mg of N- 1- 2'-(methoxycarbonylmethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate. FAB-MS: calculated for C₃₂ H₃₇ N₅ O₅ 571; found 594(M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ 1.34 (s, 3H), 1.39 (s, 3H), 2.15(m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H), 2.66 (m, 2H), 2.71 (s, 3H), 2.87(s, 2H), 4.42 (dd, 1H), 5.05 (d, 1H), 5.22 (d, 1H), 7.28 (m, 11H), 7.61(d, 1H).

EXAMPLE23 N- 1- 2'- (Methoxycarbonylmethylamino)carbonyl!amino!1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- 2'-(t-butoxycarbonylmethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideby the procedure described in Example 22, Step B. FAB-MS: calculated forC₃₂ H₃₇ N₅ O₅ 571; found 594 (M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ 1.34(s, 3H), 1.39 (s, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 2.52 (dd, 2H), 2.66(m, 2H), 2.71 (s, 3H), 2.87 (s, 2H), 4.42 (dd, 1H), 5.05 (d, 1H), 5.22(d, 1H), 7.28 (m, 11H), 7.61 (d, 1H).

EXAMPLE 24 N- 1- 2'- (Benzylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand benzyl amine by the procedures described in Example 6. ¹ H NMR (400MHz,CD₃ OD): δ 1.34 (s,3H), 1.37 (s,3H), 2.13 (m,1H), 2.33 (m,1H),2.45-2.70 (m,4H), 4.28 (s,2H), 4.42 (dd,1H), 5.00 (d,1H), 5.25 (d,1H),7.1-7.4 (m,16H), 7.62 (d,1H). FAB-MS: calculated for C₃₆ H₃₉ N₅ O₃, 589;found 590 (M+H).

EXAMPLE 25 N- 1- 2'- (Phenylaminocarbonyl)amino!1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand aniline by the procedures described in Example 6. FAB-MS: calculatedfor C₃₅ H₃₇ N₅ O₃, 578; found 598 (M+Na). ¹ H NMR (400 MHz, CD₃ OD): δ1.32 (s,3H), 1.35 (s,3H), 2.11 (m,1H), 2.30 (m,1H), 2.52 (m,2H), 2.65(m,1H), 4.40 (dd,1H), 5.03 (d,1H), 5.21 (d,1H), 6.99 (m,2H), 7.15-7.45(m,9H), 7.74 (d,1H).

EXAMPLE 26 N- 1- 2'- (Hydroxyaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from N- 1- (2'-isocyanato)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamideand O-(trimethylsilyl)hydroxylamine by the procedures described inExample 6. FAB-MS: calculated for C₂₉ H₃₃ N₅ O₄ 515: found 538 (M+Na). ¹H NMR (400 MHz, CD₃ OD): δ 1.26 (s, 1H), 1.28 (s, 3H), 2.11 (m, 1H),2.32 (m, 1H), 2.52 (dd, 2H), 2.60 (m, 2H), 4.40 (dd, 1H), 5.0 (d, 1H),5.24 (d, 1H), 7.25 (m, 11H), 8.0 (d, 1H).

EXAMPLE 27 N- 1- 2'- 4- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamidetrifluoroacetate

Step A:

4-Methyl-2'-(4-nitrophenoxy)-1,1'-biphenyl

A solution of 184 mg (1.0 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl(Example 12, Step C) in 3 mL of dimethylformamide was treated with 55 mgof 60% sodium hydride (33 mg NaH, 1.4 mmol). The reaction mixture wasstirred at room temperature for 30 minutes then treated with 169 mg(1.19 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was heatedat 100° C. for 2 hours. The reaction mixture was cooled, poured into 50mL of water and the resultant mixture was extracted with ethyl ether.The combined extracts were washed with water, dried over magnesiumsulfate, filtered and evaporated under vacuum. The residue waschromatographed on silica, eluting with hexanethyl acetate (10:1) togive 271 mg (0.89 mmol,88%) of the product. FAB-MS: calculated for C₁₉H₁₅ NO₂ 305: found 306 (M+H). ¹ H NMR (200 MHz,CDCl₃): δ 2.28 (s,3H),6.82 (d,2H), 7.19 (d,3H), 7.2-7.5 (m,5H), 8.05 (d,2H).

Step B:

4-Bromomethyl-2'-(4-nitrophenoxy)-1,1'-biphenyl

Prepared from 4-methyl-2'-(4-nitro-phenoxy)-1,1'-biphenyl by theprocedure described in Example 1, Step K. ¹ H NMR (200 MHz,CDCl₃): δ4.43 (s,2H), 6.83 (d,8Hz,2H), 7.09 (d,8Hz, 1H), 7.3-7.5 (m,7H), 8.04(d,8 Hz,2H).

Step C:

N- 1- 2'-(4-Nitrophenoxy)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!amino!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from 4-bromomethyl-2'-(4-nitrophenoxy)-1,1'-biphenyl and3-t-butoxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-butanamide (Example 1,Step I) by the procedure described in Example 1, Step Q. ¹ H NMR (200MHz,CDCl₃): δ 1.32 (s,6H), 1.38 (s,9H), 1.78 (m,1H), 2.3-2.7 (m,5H),4.47 (m,1H), 4.75 (d,15 Hz,1H), 5.13 (d,15 Hz,1H), 6.63 (d,7 Hz,1H),6.75 (d,8 Hz,2H), 7.05-7.50 (m,11H), 7.97 (s,1H), 7.98 (d,8 Hz,2H).

Step D:

N- 1- 2'-(4-Aminophenoxy)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!amino!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 282 mg (0.415 mmol) of the intermediate obtained in Step Cin 30 mL of methanol was hydrogenated at 40 psi in the presence of 5%palladium on carbon. After uptake of hydrogen was complete, the mixturewas filtered through Celite and the filtrate was evaporated under vacuumto yield 264 mg of product.

Step E:

N- 1- 2'- 4- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

A solution of 264 mg (0.40 mmol) of the intermediate obtained in Step Din 5 mL of methylene chloride under a nitrogen atmosphere was treatedwith 0.90 mL (15 mmol) of methyl isocyanate. The reaction mixture wasstirred at room temperature for 18 hours, then all volatiles wereremoved under vacuum and the residue purified by chromatography onsilica gel, eluting with ethyl acetateexane (3:1) to give 287 mg (0.40mmol, 100%) of product. ¹ H NMR (400 MHz, CD₃ OD): δ 1.24 (s,3H), 1.31(s,6H), 1.39 (s,9H), 2.00 (m,1H), 2.30 (m,1H), 2.42 (m,3H), 2.50(dd,1H), 2.73 (s,3H), 4.32 (dd,1H), 4.82 (d,1H), 5.24 (d,1H), 6.70(m,2H), 6.95 (d,1H), 7.2 (m,13H).

Step F:

N- 1- 2'- 4- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

A solution of 287 mg (0.40 mmol) of the intermediate obtained in Step Ein 3 mL of methylene chloride was treated with 1.5 mL of trifluoroaceticacid. The reaction mixture was stirred at room temperature for 1 hourthen evaporated under vacuum and the residue purified by reverse phasemedium pressure liquid chromatography on C8, eluting with methanolB 0.1%aqueous trifluoroacetic acid (50:50). Fractions containing the productwere combined, solvents removed under vacuum and the residue lyophilizedfrom water to give 165 mg (0.23 mmol,57%) of the title compound as awhite solid. FAB-MS: calculated for C₃₆ H₃₉ N₅ O₄ 605; found 628 (M+Na).¹ H NMR (400 MHz,CD₃ OD): δ 1.33 (s,3H), 1.36 (s,3H), 2.06 (m,1H), 2.26(m,1H), 2.48 (m,4H), 2.74 (s,3H), 4.36 (dd,1H), 4.8 (d,1H), 5.17 (d,1H).

EXAMPLE 28 N- 1- 2'- 2- (Methylaminocarbonyl)amino!phenoxy !1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

Step A:

4-Methyl-2'-(2-nitrophenoxy)-1,1'-biphenyl

Prepared from 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) and1-fluoro-2-nitrobenzene by the procedure described in Example 27, StepA. ¹ H NMR (200 MHz,CDCl₃): δ 2.30 (s,3H), 6.74 (dd;2,8 Hz;1H), 6.9-7.5(m,10H), 7.84 (dd;2,8 Hz;1H).

Step B:

4-Bromomethyl-2'-(2-nitrophenoxy)-1,1'-biphenyl

Prepared from 4-methyl-2'-(2-nitrophenoxy)-1,1'-biphenyl by theprocedure described in Example 1, Step K. ¹ H NMR (400 MHz,CD₃ OD): δ4.52 (s,2H), 7.4 (m,11H), 7.86 (d,1H).

Step C:

N- 1- 2'-(2-Nitrophenoxy)1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!amino!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from 4-bromomethyl-2'-(2-nitrophenoxy)-1,1'-biphenyl and3-t-butoxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-butanamide (Example 1,Step I) by the procedure described in Example 1, Step Q. ¹ H NMR (200MHz,CDCl₃): δ 1.32 (s,6H), 1.38 (s,9H), 1.78 (m,1H), 2.3-2.7 (m,5H),4.47 (m,1H), 4.75 (d,15 Hz,1H), 5.13 (d,15 Hz,1H), 6.63 (d,7 Hz,1H),6.75 (d,8 Hz,2H), 7.05-7.50 (m,B 11H), 7.97 (s,1H), 7.98 (d,8 Hz,2H).

Step D:

N- 1- 2'-(2-Aminophenoxy)1,1'-biphenyl!4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!amino!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from the intermediate obtained in Step C by the proceduredescribed in Example 27, Step D.

Step E:

N- 1- 2'- 2- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-t-butoxycarbonylamino-3-methylbutanamide

Prepared from the intermediate obtained in Step D by the proceduredescribed in Example 27, Step E.

Step F:

N- 1- 2'- 2- (Methylaminocarbonyl)amino!phenoxy!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate

The title compound was prepared from the intermediate obtained in Step Eby the procedure described in Example 27, Step F. FAB-MS: calculated forC₃₆ H₃₉ N₅ O₄ 605; found 628 (M+Na). ¹ H NMR (400 MHz,CD₃ OD): δ 1.38(s, 3H), 1.42 (s, 3H), 2.08 (m, 1H), 2.38 (m, 3H), 2.54 (dd, 2H), 2.8(s, 3H), 4.39 (dd, 1H), 4.85 (d, 1H), 5.3 (d, 1H), 6.51 (d, 1H), 5.8 dt,1H), 6.84 (dt, 1H), 7.00 (dd, 1H), 7.34 (m, 12H), 8.94 (dd, 1H).

EXAMPLE 29 N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide, trifluoroacetate

Step A:

N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-benzyloxypropyl!amino-3-methylbutanamide, trifluoroacetate

To a solution of 250 mg (0.399 mmol) of N- 1- 2'-(methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate (Example 2) in 12 mL of methanol was added 1.35 g ofpowdered 4 Å molecular sieves followed by 713 mg (4.34 mmol) of(R)-2-benzyloxypropanal (prepared from ethyl D-lactate according to theprocedure of Hanessian and Kloss, Tetrahedron Lett., 26, 1261-1264(1985).) in 2 mL of dry methanol. After adjusting the pH of thesuspension to 5.5 with glacial acetic acid, the reaction mixture wasstirred at room temperature for 3 hours. Dropwise, 2.5 mL of 1.0 Msodium cyanoborohydride in tetrahydrofuran was added and the reactionmixture stirred at room temperature for 18 hours. The reaction mixturewas filtered and the filtrate treated with 2.0 mL of trifluoroaceticacid (CAUTION| evolution of hydrogen cyanide). After stirring for 10minutes, all volatiles were removed under vacuum and the residuechromatographed on silica gel, eluting with methylenechlorideethanol/concentrated ammonium hydroxide (90:5:1) to yield 225 mg(0.339 mmol, 85%) of product. FAB-MS with Li: calculated for C₄₀ H₄₇ N₅O₄ 661: found 668 (M+Li), 662 (M+1). ¹ H NMR (400 MHz, CD₃ OD): δ 1.19(d, 3H), 1.19 (s, 3H), 1.21 (s, 3H), 2.05 (m, 1H), 2.3 (m, 1H), 2.4 (m,2H), 2.20 (s, 3H), 2.3 (m, 2H), 3.64 (m, 1H), 4.40 (dd, 1H), 4.58 (s,1H), 4.62 (d, 1H), 5.05 (d, 1H), 5.14 (d, 1H), 7.23 (m, 16H), 7.66 (d,1H).

Step B:

N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide, trifluoroacetate

A solution of 225 mg (0.339 mmol) of the intermediate obtained in Step Ain 5 mL of methanol containing 0.2 mL of trifluoroacetic acid washydrogenated at ambient temperature and 40 psi for 24 hours over 500 mgof 30% palladium on carbon. The reaction mixture was filtered throughCelite and the filtrate was evaporated under vacuum and the residuepurified by reverse phase medium pressure liquid chromatography on C8,eluting with methanol/0.1% aqueous trifluoroacetic acid (65:35).Fractions containing the product were combined, solvents removed undervacuum and the residue lyophilized from water to give 160 mg (0.23 mmol,69%) of the title compound as a white solid. FAB-MS: calculated for C₃₃H₄₁ N₅ O₄ 571: found 572 (M+H). ¹ H NMR (400 MHz, CDCl₃): δ 1.20 (d,1H), 1.36 (s, 3H), 1.37 (s, 3H), 2.15 (m, 1H), 2.34 (m, 1H), 2.34 (m,1H), 2.62 (dd, 2H), 2.63 (s, 3H), 2.68 (m, 2H), 2.80 (dd, 1H), 3.09 (dd,1H), 3.90 (m, 1H), 4.40 (dd, 1H), 5.08 (d, 1H), 5.16 (d, 1H), 7.22 (m,11H), 7.62 (d, 1H).

EXAMPLE 30 N- 1- 2'- (Morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide, trifluoroacetate

Prepared from N- 1- 2'- (morpholinocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate (Example 6) and (R)-2-benzyloxypropanal by theprocedure described in Example 29. FAB-MS: calculated for C₃₆ H₄₅ N₅ O₅627: found 650 (M+Na). ¹ H NMR (400 MHz,CDCl₃): δ 1.20 (d,3H), 1.36(s,3H), 1.39 (s,3H), 2.14 (m,1H), 2.34 (m,1H), 2.62 (dd,2H), 2.66 (m,2H,2.7 (dd,1H), 3.09 (dd,1H), 3.25 (m,4H), 3.63 (m,4H), 3.83 (m,1H), 4.39(m,1H), 5.05 (d,1H), 5.20 (d,1H), 7.29 (m,12H).

EXAMPLE 31 N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(R)-hydroxypropyl!amino-3-methylbutanamide, trifluoroacetate

Prepared from N- 1- 2'- (2-hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluomacetate (Example 8) and (R)-2-benzyloxypropanal by the proceduredescribed in Example 29. FAB-MS: calculated for C₃₄ H₄₃ N₅ O₅ 601: found602 (M+H). ¹ H NMR (400 MHz,CD₃ OD): δ 1.20 (d,3H), 1.36 (s,3H), 1.38(s,3H), 2.18 (m,1H), 2.35 (m,1H), 2.62 (dd,2H), 2.68 (m,2H), 2.78(dd,1H), 3.09 (dd,1H), 3.2 (t,2H), 3.52 (t,2H), 3.93 (m,1H), 4.40(dd,1H), 5.12 (d,1H), 5.18 (d,1H), 7.28 (m,11H), 7.65 (d,1H).

EXAMPLE 32 N- 1- 2'- (Methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide, trifluoroacetate

To a stirred solution of 368 mg (0.716 mmol) of N- 1- 2'-(methylaminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate (Example 2) in 12 mL of dry methanol under nitrogen wasadded 1.35 g of powdered 4A molecular sieves followed by a solution of0.4 g of D-glyceraldehyde acetonide (used crude as prepared according tothe procedure of L. W. Hertel, C. S. Grossman and J. S. Kroin, Synth.Comm., 21, 151-154 (1991).) in 1 mL of dry methanol. The pH of themixture was carefully adjusted to 5.5 with glacial acetic acid andtriethylamine. The reaction was stirred at room temperature for 2 hoursat which time 3.0 mL of a 1.0 M solution of sodium cyanoborohydride intetrahydrofuran was added dropwise by syringe. The reaction mixture wasstirred at room temperature for 18 hours, then filtered and the filtratetreated with 9 mL of trifluoroacetic acid and 9 mL of water. After 1hour, the reaction mixture was evaporated under vacuum and the residuepurified by reverse phase medium pressure liquid chromatography on C8,eluting with methanolB 0.1% aqueous trifluoroacetic acid (60:40).Fractions containing the product were combined, solvents removed undervacuum and the residue lyophilized from water to give 167 mg of thetitle compound as a white solid. FAB-MS: calculated for C₃₃ H₄₁ N₅ O₅587: found 589. ¹ H NMR (400 MHz, CD₃ OD): δ 1.37 (s,3H), 1.39 (s,3H),2.15 (m,1H), 2.35 (m,1H), 2.55-2.75 (m,4H), 2.64 (s,3H), 2.95 (dd,1H),3.18 (dd,1H), 3.54 (m,2H), 3.83 (m,1H), 4.42 (dd,1H), 5.08 (d,1H), 5.16(d,1H), 7.1-7.4 (m,11H), 7.61 (d,1H).

EXAMPLE 33 N- 1- 2'- (Aminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide, trifluoroacetate

The title compound was prepared from N- 1- 2'- (aminocarbonyl)amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate (Example 5) and D-glyceraldehyde acetonide according tothe procedure described in Example 32. FAB-MS: calculated for C₃₂ H₄₁ N₅O₄ 559: found 561. ¹ H NMR (400 MHz, CD₃ OD): δ 1.36 (s, 1H), 1.38 (s,3H), 2.15 (m, 1H), 2.34 (m, 1H), 2.62 (dd, 2H), 2.68 (m, 2H), 2.95 (dd,1H), 3.18 (dd, 1H), 3.52 (m, 2H), 3.82 (m, 1H), 4.40 (dd, 1H), 5.05 (d,1H), 5.06 (d, 1H), 7.25 (m, 11H), 7.60 (d, 1H).

EXAMPLE 34 N- 1- 2'- (2-Hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-2(S),3-dihydroxypropyl!amino-3-methylbutanamide, trifluoroacetate

The title compound was prepared from N- 1- 2'-(2-hydroxyethylamino)carbonyl!amino!1,1'-biphenyl!-4-yl!methyl!-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-3-amino-3-methylbutanamide,trifluoroacetate (Example 8) and D-glyceraldehyde acetonide according tothe procedure described in Example 32.

EXAMPLE 35 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3R-yl!propanamide,hydrochloride

Step A:

2-Benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from N-carbobenzyloxy-2-methylalanine and3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one (Example 1, Step E)substituting benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate forbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateaccording to the procedure described in Example 1, Step I. ¹ H NMR (200MHz, CDCl₃): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m,3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H), 8.65(s, 1H). FAB-MS: calculated for C₂₂ H₂₅ N₃ O₄ 395; found 396 (M+H,100%).

Step B:

4-Bromobenzyl-t-butyldiphenylsilyl ether

To a solution of 28.2 g (0.150 mol) of 4-bromobenzylalcohol in 470 mL ofdry dimethylformamide under nitrogen atmosphere was added 31.4 mL (0.225mol) of triethylamine. The reaction mixture was cooled to 0° C. and 43mL (0.17 mol) of t-butylchlorodiphenylsilane was added dropwise byaddition funnel. The reaction mixture was stirred at ambient temperatureovernight then poured into a separatory funnel containing 1 L of diethylether and 500 mL of water. To this mixture was added 125 mL of 2 Naqueous hydrochloric acid. The layers were separated and the aqueouslayer was extracted with diethyl ether (2×350 mL). The organic extractswere combined, washed with water (2×250 mL) and dried over magnesiumsulfate. The solids were removed by filtration and the solvent removedunder vacuum to give an oil which crystallized on standing. The flaskcontaining the crude product was placed in the freezer overnight thentriturated with a minimal amount of methanol and filtered. The solid wasair dried for several hours then dried under vaccuum overnight to afford59.5 g (93%) of product as an off-white solid (mp 44°-47° C.). ¹ H NMR(200 MHz, CDCl₃): δ 1.15 (s, 9H), 4.76 (s, 2H), 7.25 (d, 8 Hz, 2H), 7.45(m, 8H), 7.75 (m, 4H). FAB-MS: calculated for C₂₃ H₂₅ BrOSi 424; found425 (M+H, 7%).

Step C:

4-(t-Butyldiphenylsiloxymethyl)phenylboronic acid

To a solution of 20 g (47 mmol) of 4-bromobenzyl-t-butyldiphenyl silylether (Step B) in 200 mL of dry tetrahydrofuran under a nitrogenatmosphere at -78° C. was added dropwise by syringe 19.74 mL (49.35mmol) of a 2.5 M solution of n-butyl lithium in hexanes over twentyminutes. The resulting mixture was stirred for thirty minutes, then 11.6mL (50.3 mmol) of triisopropyl borate was added by syringe. The reactionmixture was stirred at -78° C. for thirty minutes then slowly warmed toroom temperature and stirred for an additional two hours. The reactionmixture was then quenched by the addition of 750 mL of water containing100 mL of concentrated hydrochloric acid and 500 mL of diethyl ether.The mixture was stirred for one hour and then the organic layer wasseparated. The aqueous layer was extracted with diethyl ether (2×400mL). The combined ether extracts were washed with saturated aqueoussodium chloride (4×100 mL), dried over magnesium sulfate and filtered.The solvent was removed under vacuum to give an oil which wascrystallized by dissolving in hexanes and evaporation of the solventunder vacuum to afford 15.6 g (85%) of product as a white solid (mp171°-174° C.). ¹ H NMR (200 MHz, CDCl₃): δ 1.11 (s, 9H), 4.86 (s, 2H),7.40 (m, 6H), 7.58 (d, 8 Hz, 2H), 7.70 (m, 4H), 8.22 (d, 8 Hz, 2H).FAB-MS: calculated for C₂₃ H₂₇ BrO₃ Si 390; found 372 (M-H₂ O).

Step D:

N-(t-Butoxycarbonyl)-2-bromobenzylamine

To a slurry of 8.88 g (39.9 mmol) of 2-bromobenzylamine hydrochloride in100 mL of dry methylene chloride under a nitrogen atmosphere was addedby syringe 12.24 mL (87.80 mmol) of triethylamine. The resultingsolution was stirred at 0° C. for five minutes then treated with 9.6 g(44 mmol) of di-t-butyldicarbonate. The reaction was stirred at roomtemperature for two hours then diluted with 350 mL of methylenechloride. The solution was washed with water (2×150 mL), saturatedaqueous ammonium chloride (150 mL), saturated aqueous sodium bicarbonate(4×150 mL) and saturated aqueous sodium chloride (150 mL), dried oversodium sulfate and filtered. The solvent was removed under vacuum togive an oil which was crystallized by dissolving in hot hexanes,filtering and cooling the solution. The product was filtered and driedunder vacuum to afford 8.66 g (90%) of the product as a white solid (mp51°-53° C.). ¹ H NMR (200 MHz, CDCl₃): δ 1.41 (s, 9H), 4.37 (d, 5 Hz,2H), 5.00 (s, 1H), 7.10 (m, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.40 (d, 6Hz, 1H). FAB-MS: calculated for C₁₂ H₁₆ BrNO₂ 285; found 286 (M+H).

Step E:

2'- (t-Butoxycarbonylamino)methyl!-4-(t-butyldiphenylsiloxy)methyl!-1,1'-biphenyl

To a solution of 3.2 g (8.2 mmol) of4-(t-butyldiphenylsilyoxymethyl)phenylboronic acid (Step C) in 64 mL ofbenzene was added 2.2 mL of water, 6.4 mL of 5 N aqueous sodiumhydroxide, and 8.3 mL of isopropanol. To this mixture was added 180 mg(0.16 mmol) of tetrakis(triphenylphosphine) palladium and 2.20 g (7.81mmol) of N-(t-butoxycarbonyl)-2-bromobenzylamine (Step D). The resultingmixture was heated under nitrogen at reflux for 2 hours then cooled toroom temperature. The reaction mixture was diluted with 100 mL of water,transferred to a separatory funnel and extracted with ether (3×150 mL).The combined ether extracts were washed with saturated aqueous sodiumbicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL),dried over magnesium sulfate and filtered. The solvent was removed undervacuum to give a crude product which was purified by columnchromatography on silica gel eluting with hexanesthyl acetate (9:1) toafford 4.31 g (100%) of the product as a clear oil. ¹ H NMR (200 MHz,CDCl₃): δ 1.11 (s, 9H), 1.41 (s, 9H), 4.27 (d, 6 Hz, 2H), 4.45 (m, 1H),4.81 (s, 2H), 7.20-7.49 (m, 14H), 8.72 (m, 4H). FAB-MS: calculated forC₃₅ H₄₁ NO₃ Si 551; found 552 (M+H).

Step F:

2'- (t-Butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol

To a solution of 3.85 g (7.00 mmol) of 2'-(t-butoxycarbonylamino)methyl!-4-(t-butyldiphenylsiloxy)methyl!-1,1'-biphenyl (Step E) in 25 mL of drytetrahydrofuran under a nitrogen atmosphere was added by syringe 10.5 mL(0.530 mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride intetrahydrofuran. The reaction mixture was stirred for two hours thendiluted with 700 mL of diethyl ether. The mixture was washed with water(3×150 mL), saturated aqueous sodium bicarbonate (50 mL), saturatedaqueous sodium chloride (50 mL), then dried over magnesium sulfate andfiltered. The solvent was removed under vacuum to give an oil which waspurified by column chromatography on silica gel eluting with hexanesthylacetate (55:45) to afford 2.02 g (92%) of the product as a white solid(mp 89°-93° C.). ¹ H NMR (200 MHz, CDCl₃): δ 1.40 (s, 9H), 2.50 (s, 2H),4.20 (s, 2H), 4.70 (s, 2H), 7.18-7.45 (m, 8H). FAB-MS: calculated forC₁₉ H₂₃ NO₃ 313; found 314 (M+H).

Step G:

2'- (t-Butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol,methanesulfonate ester

To solution of 53 mg (0.17 mmol) of 2'-(t-butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol (Step E) in 1 mLof dry methylene chloride under nitrogen atmosphere at 0° C. was addedby syringe 0.035 mL (0.25 mmol) of triethylamine followed by 0.016 mL(0.20 mmol) of methanesulfonyl chloride. The reaction mixture wasstirred for 2 hours at 0° C. then diluted with 75 mL of methylenechloride, washed with water, saturated aqueous sodium bicarbonate,saturated aqueous sodium chloride, dried over sodium sulfate andfiltered. The solvent was removed under vacuum to give 61 mg (97%) ofthe product as a white solid which was used in the next step withoutfurther purification. ¹ H NMR (200 MHz, CDCl₃): δ 1.38 (s, 9H), 2.95 (s,3H), 4.20 (d, 5 Hz, 2H), 4.65 (s, 1H), 5.25 (s, 2H), 7.18-7.50 (m, 8H).FAB-MS: calculated for C₂₀ H₂₅ NO₅ S 391; found 392 (M+H).

Step H:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1- 2'-(t-butoxycarbonylamino)methyl!1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide

To a solution of 819 mg (2.07 mmol) of2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!propanamide (Step A) in7.0 mL of dry dimethylformamide under nitrogen at 0° C. was added 83 mg(2.1 mmol) of 60% sodium hydrideil dispersion. After stirring for 15minutes, a solution of 810 mg (2.1 mmol) of 2'-(t-butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol,methanesulfonate ester (Step F) in 2.0 mL of dimethylformamide was addedby cannula. The flask which originally contained the methanesulfonateester was rinsed with 1.0 mL of dimethylformamide which was added to thereaction mixture. After stirring at 0° C. for 15 minutes, the reactionmixture was diluted with 400 mL of ethyl acetate and 50% saturatedammonium chloride. The mixture was transferred to a separatory funneland the aqueous layer was separated. The organic layer was washed with100 mL of saturated aqueous sodium bicarbonate and saturated aqueoussodium chloride. The organic layer was dried over magnesium sulfate,filtered and the solvent removed under vacuum. The residue was purifiedby flash chromatography on silica gel eluting with ethyl acetate/hexane(55:45) to afford 1.2 g (84%) of the product as a white foam. ¹ H NMR(200 MHz, CDCl₃): δ 1.38 (s, 9H), 1.48 (s, 3H), 1.52 (s, 3H), 1.78 (s,1H), 2.35-2.70 (m, 3H), 4.18 (d, 6 Hz, 2H), 4.38-4.62 (m, 2H), 4.82 (d,16 Hz, 1H), 5.05 (s, 2H), 5.25 (d, 16 Hz, 1H), 5.32 (s, 1H), 7.08 (d, 6Hz, 1H), 7.12-7.43 (m, 18H). FAB-MS: calculated for C₄₁ H₄₆ N₄ O₆ 690;found 691(M+H).

Step I:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1-2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,hydrochloride

To a solution of 9.83 g (0.55 mmol) of2-benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1- 2'-(t-butoxycarbonylamino)methyl!1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide (Step H)in 170 mL of methanol was added 120 mL of 9 N aqueous hydrochloric acid.Periodically 10 mL portions of methanol were added to the reactionmixture to dissolve precipitates which form during the reaction (50 mLtotal). The reaction mixture was stirred overnight at room temperaturethen the solvent was removed under vacuum. The resulting oil wasdissolved in methanol and the solvent was removed under vacuum to afford8.57 g (96%) of the title compound as an off-white foam. ¹ H NMR (200MHz, CD₃ OD): δ 1.40 (s, 6H), 1.90 (m, 1H), 2.20-2.65 (m, 3H), 4.02 (s,2H), 4.32 (m, 1H), 4.96 (d, 16 Hz, 1H), 5.00 (s, 2H), 5.25(d, 16 Hz,1H), 7.08-7.65 (m, 17H). FAB-MS: calculated for C₃₆ H₃₈ N₄ O₄ 590; found591(M+H, 100%).

Step J:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

To a solution of 8.57 g (13.7 mmol) of2-benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1-2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,hydrochloride (Step I) in 75 mL of dry methylene chloride under nitrogenatmosphere was added 2.28 mL (16.4 mmol) of triethylamine followed by0.89 mL (15 mmol) of methyl isocyanate. After stirring at roomtemperature for 45 minutes the solvent was removed under vacuum. Theresulting material was dissolved in methylene chloride and purified byflash column chromatography on silica gel eluting with ethylacetateethanol (96:4) to afford 7.73 g (87%) of product as a white foam.¹ H NMR (200 MHz, CD₃ OD): δ 1.39 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m,3H), 2.63 (s, 3H), 4.13 (s, 2H), 4.36 (m, 1H), 4.86 (d, 15 Hz, 1H), 4.85(s, 2H), 5.32 (d, 15 Hz, 1H), 7.08-7.43 (m, 17H). FAB-MS: calculated forC₃₈ H₄₁ N₅ O₅ 647; found 648(M+H, 80%).

Step K:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,hydrochloride

To a solution of 5.00 g (7.72 mmol) of2-benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl! 1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide (Step J) in 100 mL of drymethanol was added 0.50 g (0.1 equiv. by weight) of palladium hydroxide.The mixture was stirred under hydrogen atmosphere for 2 hours. Themixture was filtered through Celite. The filter pad was washed with 50mL of methanol. The filtrate was combined and the solvent was removedunder vacuum. The resulting oil was dissolved in 50 mL of methanol andtreated with 17 mL (8.5 mmol) of a 0.499 N aqueous hydrochloric acidsolution. The solvent was removed under vacuum to give a solid which wascrystallized by refluxing in 480 mL of acetonitrilethanol (7:1). Themixture was cooled to room temperature with gentle stirring. After 3hours the solids were filtered and washed with 80 mL of ice coldacetonitrile/ethanol (7:1) and then air dried for 3 hours. The resultingsolid was dissolved in 40 mL of water, filtered and lyophilizedovernight to afford 3.78 g (89%) of the title compound as a white solid.¹ H NMR (400 MHz, CD₃ OD): δ 1.55 (s, 3H), 1.64 (s, 3H), 2.28 (m, 2H),2.62 (m, 2H), 2.67 (s, 3H), 4.16 (dd; 16, 14 Hz; 2H), 4.39 (dd; 12, 8Hz; 1H), 5.00 (d, 15 Hz, 1H), 5.22 (d, 15 Hz, 1H), 7.14 (d, 7 Hz, 1H),7.20-7.41 (m, 11H). FAB-MS: calculated for C₃₀ H₃₅ N₅ O₃ 513; found 514(M+H, 100%).

EXAMPLE 36 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-hydroxyethyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1-2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

To a solution of 380 mg (0.55 mmol) of2-benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1- 2'-(t-butoxycarbonylamino)methyl!1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide (Example35, Step H) in 2 mL of dry methylene chloride was added 5 drops ofanisole followed by 2 mL of trifluoroacetic acid. The reaction mixturewas stirred for 1.5 hours at room temperature at which time the solventwas removed under vacuum. The resulting oil was dissolved in 5 mL ofcarbon tetrachloride and the solvent was removed under vacuum. Theprocess was repeated with 5 mL of chloroform followed by 5 mL ofmethylene chloride to give 427 mg (>100%) of the product containingminor amount of anisole) as an off-white foam. ¹ H NMR (200 MHz, CDCl₃):δ 1.45 (s, 6H), 1.90 (m, 1H), 2.25-2.65 (m, 3H), 4.12 (s, 2H), 4.38 (m,1H), 4.85 (d, 16 Hz, 1H), 4.96 (s, 2H), 5.05 (d, 16 Hz, 1H), 5.55 (s,1H), 6.91 (m, 1H), 7.05-7.60 (m, 19H). FAB-MS: calculated for C₃₆ H₃₈ N₄O₄ 590; found 591 (M+H, 100%).

Step B:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-hydroxyethyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

To a solution of 160 mg (0.23 mmol) of2-benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1-2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Step A) in 1 mL of dry methylene chloride undernitrogen atmosphere was added 0.063 mL (0.45 mmol) of triethylaminefollowed by 0.039 mL (0.25 mmol) of 2-isocyanatoethyl methacrylate. Thereaction mixture was stirred at room temperature for 30 minutes then thesolvent was removed under vacuum.

The residue was dissolved in 2 mL of tetrahydrofuranater (3:1) and tothe resulting solution was added 42 mg (1.0 mmol) of lithium hydroxidemonohydrate. After stirring at room temperature for 3 hours the reactionmixture was diluted with 100 mL of ethyl acetate and washed with 50 mLof brine. The organic layer was dried over magnesium sulfate, filteredand the solvent removed under vacuum to afford 149 mg (97%) of theproduct as a white foam. ¹ H NMR (200 MHz, CDCl₃): δ 1.48 (m, 9H), 1.82(m, 1H), 2.10-2.70 (m, 3H), 3.05 (m, 2H), 3.15 (t, 4 Hz, 2H), 2.55 (t, 4Hz, 2H), 4.20 (s, 2H), 4.45 (m, 1H), 4.68 (s, 1H), 5.03 (s, 2H), 5.38(s, 1H), 7.05-7.43 (m, 19H). FAB-MS: calculated for C₃₉ H₄₃ N₅ O₆ 677;found 678(M+H, 60%).

Step C:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-hydroxyethyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

To a solution of 149 mg (0.22 mmol) of2-benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-hydroxyethyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step B) in 3 mL of dry methanol was added 30 mg (0.2 equiv. by weight)of palladium hydroxide. The mixture was stirred under hydrogenatmosphere for 2 hours. The mixture was filtered through Celite. To thefiltrate was added 3 drops of trifluoroacetic acid and the solvent wasremoved under vacuum to give a solid which was purified by reverse phasemedium pressure liquid chromatography on C-8 eluting with methanolB 0.1%aqueous trifluoroacetic acid (60:40) to afford 87 mg (60%) of the titlecompound as a white solid. ¹ H NMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H),1.62 (s, 3H), 2.28 (m, 2H), 2.60 (m, 2H), 3.19 (t, 6 Hz, 2H), 3.53 (t, 6Hz, 2H), 4.15 (s, 2H), 4.39 (dd, 12, 8 Hz; 1H), 4.99 (d, 15 Hz, 1H),5.20 (d, 15 Hz, 1H), 7.10-7.41 (m, 12H). FAB-MS: calculated for C₃₁ H₃₇N₅ O₄ 543; found 544(M+H, 80%).

EXAMPLE 37 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-methoxyphenyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-methoxyphenyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

To a solution of 100 mg (0.142 mmol) of2-benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-2-oxo-1-2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) in 2 mL of dry methylene chlorideunder nitrogen atmosphere was added 0.040 mL (0.28 mmol) oftriethylamine followed by 0.021 mL (0.16 mmol) of 2-methoxyphenylisocyanate The reaction mixture was stirred at room temperature for 30minutes, diluted with 100 mL of ethyl acetate, washed with 25 mL ofsaturated aqueous ammonium chloride, 25 mL of saturated aqueous sodiumbicarbonate and 25 mL of brine. The organic layer was dried overmagnesium sulfate, filtered and the solvent removed under vacuum toafford 102 mg (97%) of the product as a white foam. ¹ H NMR (200 MHz,CD₃ OD): δ 1.38 (s, 6H), 1.80 (m, 1H), 2.15-2.50 (m, 3H), 3.80 (s, 3H),4.19 (s, 2H), 4.27 (m, 1H), 4.68 (d, 16 Hz, 1H), 5.00 (s, 2H), 5.30 (d,16 Hz, 1H), 6.90 (m, 3H), 7.10-7.45 (m, 17H), 7.92 (m, 1H). FAB-MS:calculated for C₄₄ H₄₅ N₅ O₆ 739; found 740 (M+H, 60%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-methoxyphenyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'-((2-methoxyphenyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide (StepA) according to the procedure described in Example 36, Step C. ¹ H NMR(200 MHz, CD₃ OD): δ 1.52 (s, 3H), 1.61 (s, 3H), 2.22 (m, 2H), 2.65 (m,2H), 3.82 (s, 3H), 4.21 (s, 2H), 4.36 (dd; 12, 8 Hz; 1H), 4.93 (d, 15Hz, 1H), 5.20 (d, 15 Hz, 1H), 6.78-6.95 (m, 3H), 7.12-7.45 (m, 12H) 7.91(dd, 4, 1 Hz; 1H). FAB-MS: calculated for C₃₆ H₃₉ N₅ O₄ 605; found606(M+H, 100%).

EXAMPLE 38 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-hydroxyphenyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-((2-hydroxyphenyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

To a solution of 48 mg (0.067 mmol) of 2-amino-2-methyl- N-2,3,4,5-tetrahydro-1- 2'- ((2-methoxyphenyl)amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 37, Step B) in 2 mL of dry methylene chlorideunder nitrogen atmosphere was added 0.33 mL (0.33 mmol) of a 1.0 Msolution of boron tribromide in methylene chloride. The reaction mixturewas stirred at room temperature for one hour and then quenched by theaddition of 1 mL of water. The solvent was removed under vacuum and theresidue was dissolved in 2 mL of methanol and treated with 2 drops oftrifluoroacetic acid. The solvent was removed under vacuum and theresidue was purified by reverse phase medium pressure liquidchromatography on C-8, eluting with methanolB 0.1% aqueoustrifluoroacetic acid (60:40), to afford 37 mg (60%) of the titlecompound as a white solid. ¹ H NMR (200 MHz, CD₃ OD): δ 1.52 (s, 3H),1.61 (s, 3H), 2.22 (m, 2H), 2.58 (m, 2H), 4.22 (s, 2H), 4.36 (dd; 12, 8Hz; 1H), 4.93 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 6.67-6.85 (m, 3H),7.12-7.48 (m, 12H) 7.62 (m, 1H). FAB-MS: calculated for C₃₅ H₃₇ N₅ O₄591; found 592 (M+H, 60%).

EXAMPLE 39 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) and trimethylsilyl isocyanateaccording to the procedure described in Example 37, Step A. ¹ H NMR (200MHz, CD₃ OD): δ 1.40 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m, 3H), 4.12 (s,2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz,1H), 7.05-7.43 (m, 17H). FAB-MS: calculated for C₃₇ H₃₉ N₅ O₅ 633; found644 (M+H, 100%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58(m, 2H), 4.13 (s, 2H), 4.37 (dd, 12, 8 Hz; 1H), 4.97 (d, 15 Hz, 1H),5.20 (d, 15 Hz, 1H), 7.10-7.41 (m, 12H). FAB-MS: calculated for C₂₉ H₃₃N₅ O₃ 499; found 500 (M+H, 100%).

EXAMPLE 40 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(benzylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(benzylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) and benzyl isocyanate according tothe procedure described in Example 37, Step A. ¹ H NMR (200 MHz, CD₃OD): δ 1.38 (s, 6H), 1.82 (m, 1H), 2.15-2.55 (m, 3H), 4.14 (s, 2H), 4.24(s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15Hz, 1H), 7.05-7.42 (m, 22H). FAB-MS: calculated for C₄₄ H₄₅ N₅ O₅ 723;found 724 (M+H, 100%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(benzylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (benzylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!- 2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58(m, 2H), 4.17 (s, 2H), 4.26 (s, 2H), 4.37 (dd, 11, 8 Hz; 1H), 4.96 (d,15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.10-7.41 (m, 17H). FAB-MS: calculatedfor C₃₆ H₃₉ N₅ O₃ 589; found 590 (M+H, 80%).

EXAMPLE 41 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(1-propylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(1-propylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) and 1-propyl isocyanate accordingto the procedure described in Example 37, Step A. ¹ H NMR (200 MHz, CD₃OD): δ 0.86 (t, 7.5 Hz, 3H), 1.39 (s, 6H), 1.42 (m, 2H), 1.82 (m, 1H),2.19-2.55 (m, 3H), 3.01 (t, 7 Hz, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85(d, 15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H),7.63 (d, 8 Hz, 1H). FAB-MS: calculated for C₄₀ H₄₅ N₅ O₅ 675; found 676(M+H, 85%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(1-propylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (1-propylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 0.87 (t, 7 Hz, 3H), 1.44 (dd; 16, 8 Hz; 2H),1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58 (m, 2H), 3.08 (t, 7 Hz,2H), 4.14 (s, 2H), 4.37 (dd; 12, 9 Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.20(d, 15 Hz, 1H), 7.10-7.41 (m, 12H). FAB-MS: calculated for C₃₂ H₃₉ N₅ O₃541; found 542 (M+H, 100%).

EXAMPLE 42 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(1-methylethyl)amino!carbonyl!-amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(1-methylethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) and isopropyl isocyanate accordingto the procedure described in Example 37, Step A. ¹ H NMR (200 MHz, CD₃OD): δ 1.06 (d, 6.5 Hz, 6H), 1.39 (s, 6H), 1.82 (m, 1H), 2.19-2.58 (m,3H), 3.74 (m, 1H), 4.12 (s, 2H), 4.32 (m, 1H), 4.87 (d, 15 Hz, 1H), 5.01(s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H). FAB-MS: calculated forC₄₀ H₄₅ N₅ O₅ 675; found 676(M+H, 80%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(1-methylethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (1-methylethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.06 (d, 6.5 Hz, 6H), 1.53 (s, 3H), 1.62 (s,3H), 2.25 (m, 2H), 2.58 (m, 2H), 3.74 (m, 1H), 4.14 (s, 2H), 4.37 (dd,12, 8 Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.10-7.41 (m,12H). FAB-MS: calculated for C₃₂ H₃₉ N₅ O₃ 541; found 542 (M+H, 100%).

EXAMPLE 43 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) and ethyl isocyanate according tothe procedure described in Example 37, Step A. ¹ H NMR (200 MHz, CD₃OD): δ 1.03 (t, 7 Hz, 3H), 1.39 (s, 6H), 1.82 (m, 1H), 2.18-2.58 (m,3H), 3.07 (q, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.87 (d, 15 Hz, 1H), 5.00(s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H). FAB-MS: calculated forC₃₉ H₄₃ N₅ O₅ 661; found 662 (M+H, 100%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(1-ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (1-ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!- 2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.05 (t, 7 Hz, 3H), 1.53 (s, 3H), 1.62 (s, 3H),2.25 (m, 2H), 2.58 (m, 2H), 3.09 (q, 2H), 4.14 (s, 2H), 4.37 (dd, 11, 8Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.10-7.41 (m, 12H).FAB-MS: calculated for C₃₁ H₃₇ N₅ O₃ 527; found 528 (M+H, 100%).

EXAMPLE 44 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(N,N-dimethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(N,N-dimethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,hydrochloride (Example 35, Step I) and dimethylcarbamyl chlorideaccording to the procedure described in Example 37, Step A. ¹ H NMR (200MHz, CD₃ OD): δ 1.39 (s, 6H), 1.82 (m, 1H), 2.18-2.58 (m, 3H), 2.81 (s,6H), 4.20 (d, 5 Hz, 2H), 4.32 (m, 1H), 4.86 (d, 15 Hz, 1H), 5.01 (s,2H), 5.31 (d, 15 Hz, 1H), 6.40 (t, 5 Hz, 1H), 7.06-7.40 (m, 17H).FAB-MS: calculated for C₃₉ H₄₃ N₅ O₅ 661; found 662 (M+H, 80%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(N,N-dimethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'-(N,N-dimethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58(m, 2H), 2.83 (s, 6H), 4.22 (s, 2H), 4.38 (dd, 11, 9 Hz; 1H), 4.98 (d,15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.10 (m, 1H), 7.17-7.37 (m, 11H).FAB-MS: calculated for C₃₁ H₃₇ N₅ O₃ 527; found 528 (M+H, 100%).

EXAMPLE 45 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(4-morpholino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(4-morpholino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,hydrochloride (Example 35, Step I) and 4-morpholinocarbonyl chlorideaccording to the procedure described in Example 37, Step A. ¹ H NMR (200MHz, CDCl₃): δ 1.45 (s, 3H), 1.47 (s, 3H), 1.80 (m, 1H), 2.35-2.68 (m,3H), 3.14 (t, 5 Hz, 2H), 3.58 (t, 5 Hz, 2H), 4.32 (d, 5 Hz, 2H), 4.45(dd; 12, 7 Hz; 1H), 4.86 (d, 15 Hz, 1H), 5.03 (s, 2H), 5.20 (d, 15 Hz,1H), 5.43 (s, 1H), 6.40 (t, 5 Hz, 1H), 7.05-7.42 (m, 19H). FAB-MS:calculated for C₄₁ H₄₅ N₅ O₆ 703; found 704 (M+H, 80%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(4-morpholino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (4-morpholino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58(m, 2H), 3.27 (t, 5 Hz, 2H), 3.58 (t, 5 Hz, 2H), 4.24 (s, 2H), 4.37 (dd;11, 8 Hz; 1H), 4.99 (d, 15 Hz, 1H), 5.19 (d, 15 Hz, 1H), 7.10 (m, 1H),7.17-7.40 (m, 11H). FAB-MS: calculated for C₃₃ H₃₉ N₅ O₄ 569; found 570(M+H, 100%).

EXAMPLE 46 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethoxycarbonyl)methylamino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethoxycarbonyl)methylamino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

To a slurry of 200 mg (0.284 mmol) of 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) in 1.0 mL of dry methylenechloride under a nitrogen atmosphere was added 0.080 mL (0.57 mmol) oftriethylamine. The mixture was stirred at room temperature for 30minutes (mixture A).

In a separate flask was placed 59.4 mg (0.426 mmol) of glycine ethylester hydrochloride in 2.0 mL of dry methylene chloride under a nitrogenatmosphere. To this slurry was added 0.080 mL (0.57 mmol) oftriethylamine. After 5 minutes, 69 mg (0.43 mmol) of1,1'-carbonyldiimidazole was added. The resulting mixture was stirred atroom temperature for 15 minutes then the previously prepared aminesolution (mixture A) was added via cannula to the reaction mixture.After stirring for 24 hours at room temperature, the reaction mixturewas diluted with 100 mL of ethyl acetate, washed with 25 mL of saturatedaqueous ammonium chloride, 25 mL of saturated sodium bicarbonate and 25mL of brine. The organic layer was removed, dried over magnesiumsulfate, filtered and the solvent removed under vacuum. The resultingmaterial was purified by flash column chromatography on silica geleluting with ethyl acetateexanes (90:10) to afford 149 mg (73%) of theproduct as a white foam. ¹ H NMR (200 MHz, CD₃ OD): δ 1.22 (t, 7 Hz,3H), 1.39 (s, 6H), 1.82 (m, 1H), 2.15-2.55 (m, 3H), 3.81 (s, 2H), 4.13(m, 4H), 4.32 (m, 1H), 4.86 (d, 15 Hz, 1H), 5.01 (s, 2H), 5.32 (d, 15Hz, 1H), 7.08-7.43 (m, 17H). FAB-MS: calculated for C₄₁ H₄₅ N₅ O₇ 719;found 720 (M+H, 50%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethoxycarbonyl)methylamino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'-(ethoxycarbonyl)methylamino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.22 (t, 7 Hz, 3H), 1.53 (s, 3H), 1.62 (s, 3H),2.25 (m, 2H), 2.58 (m, 2H), 3.82 (s, 2H), 4.24 (m, 4H), 4.38 (dd; 12, 9Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.10-7.40 (m, 12H).FAB-MS: calculated for C₃₃ H₃₉ N₅ O₅ 585; found 586 (M+H, 100%).

EXAMPLE 47 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(carboxymethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(benzyloxycarbonyl)methylamino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Example 36, Step A) and glycine benzyl esterhydrochloride according to the procedure described in Example 46, StepA. ¹ H NMR (200 MHz, CD₃ OD): δ 1.38 (s, 6H), 1.82 (m, 1H), 2.18-2.60(m, 3H), 3.86 (s, 2H), 4.13 (s, 2H), 4.32 (m, 1H), 4.84 (d, 15 Hz, 1H)i4.99 (s, 2H), 5.11 (s, 2H), 5.30 (d, 15 Hz, 1H), 7.05-7.41 (m, 22H).FAB-MS: calculated for C₄₆ H₄₇ N₅ O₇ 781; found 782 (M+H, 90%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(carboxymethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'-(benzyloxycarbonyl)methylamino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.59(m, 2H), 3.82 (s, 2H), 4.15 (s, 2H), 4.38 (dd; 12, 9 Hz; 1H), 4.97 (d,15 Hz, 1H), 5.19 (d, 15 Hz, 1H), 7.10-7.43 (m, 12H). FAB-MS: calculatedfor C₃₁ H₃₅ N₅ O₅ 557; found 558 (M+H, 25%).

EXAMPLE 48 3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate

Step A:

2,2-Dimethylbutanedioic acid, 4-methyl ester

2,2-Dimethylsuccinic acid (20 g, 140 mmol) dissolved in 200 mL ofabsolute methanol at 0° was treated dropwise with 2 mL of concentratedsulfuric acid. After the addition was complete, the mixture was allowedto warm to room temperature and stirred for 16 hours.

The mixture was concentrated under vacuum to 50 mL and slowly treatedwith 200 mL of saturated aqueous sodium bicarbonate. The mixture waswashed with hexane (3×) and the aqueous layer removed and cooled in anice bath. The mixture was acidified to pH 2 by slow addition of 6 N HClthen extracted with ether (8×). The combined extracts were washed withbrine, dried over magnesium sulfate, filtered and solvents removed undervacuum. The residue was dried at room temperature under vacuum to afford14.7 g (91.8 mmol, 67%) of a viscous oil that slowly solidified uponstanding. ¹ H NMR analysis indicates the product is a mixture of thedesired compound and 15% of the isomeric 2,2-dimethylbutanedioic acid,1-methyl ester. NMR (200 MHz, CDCl₃) of desired compound: δ 1.29 (s,6H), 2.60 (s, 2H), 3.66 (s, 3H). NMR (200 MHz, CDCl₃) isomer: δ 1.28 (s,6H), 2.63 (s, 2H), 3.68 (s, 3H).

Step B:

3- Benzyloxycarbonylamino!-3-methylbutanoic acid, methyl ester

To 14.7 g (91.8 mmol) of 2,2-dimethylbutanedioic acid-4-methyl ester(Step A), containing 15% of the isomeric 1-methyl ester compound, in 150mL of benzene was added 13 mL of triethylamine (9.4 g, 93 mmol, 1.01 eq)followed by 21.8 mL of diphenylphosphoryl azide (27.8 g, 101 mmol, 1.1eq). The mixture was heated under nitrogen at reflux for 45 minutes then19 mL (19.9 g, 184 mmol, 2 eq) of benzyl alcohol was added and refluxingcontinued for 16 hours.

The mixture was cooled, filtered and the filtrate concentrated to aminimum volume under vacuum. The residue was redissolved in 250 mL ofethyl acetate, washed with water, saturated aqueous sodium bicarbonate(2×) and brine. The organic layer was removed, dried over magnesiumsulfate, filtered and the filtrate concentrated to a minimum volumeunder vacuum. The crude product was purified by medium pressure liquidchromatography on silica, eluting with hexanethyl acetate (4:1), toafford 18.3 g (68.9 mmol, 75%) of the product as a pale yellow liquid inaddition to a small amount of pure 3-benzyloxycarbonylamino!-2,2-dimethylpropanoic acid, methyl ester. ¹ HNMR (200 MHz, CDCl₃) of major product: δ 1.40 (s, 6H), 2.69 (s, 2H),3.63 (s, 3H), 5.05 (s, 2H), 5.22 (br s, 1H), 7.32 (s, 5H). ¹ H NMR (200MHz, CDCl₃) of 3- benzyloxycarbonylamino!-2,2-dimethylpropanoic acid,methyl ester (200 MHz, CDCl₃): δ 1.19 (s, 6H), 3.30 (d, 7 Hz, 2H;resonance collapses to singlet in CD₃ OD), 3.67 (s, 3H), 5.09 (s, 2H),5.22 (br s, 1H; resonance absent in CD₃ OD), 7.3 (br s,5H).

Step C:

3-Benzyloxycarbonylamino-3-methylbutanoic acid

A solution of 18.3 g (68.9 mmol) of methyl3-benzyloxycarbonylamino-3-methylbutanoate (Step B) in 20 mL of methanolat room temperature was treated dropwise with 51 mL of 2 N NaOH (102mmol, 1.5 eq). The mixture was stirred at room temperature for 16 hoursthen transferred to a separatory funnel and washed with hexane (3×). Theaqueous layer was removed, cooled to 0° and slowly acidified to pH 2(paper) by dropwise addition of 6 N HCl. This mixture was extracted withether (6×); combined extracts were washed with 1 N HCl and brine, thendried over magnesium sulfate, filtered and solvent removed under vacuumto afford 17.3 g (68.7 mmol, 99%) of the product. ¹ H NMR (200 MHz,CDCl₃): δ 1.42 (s, 6H), 2.77 (s, 2H), 5.06 (s, 2H), 5.2 (br s, 1H), 7.3(s, 5H).

Step D:

3-Benzyloxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide

Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid (Step C)and 3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one (Example 1, StepE) substituting benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate forbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateaccording to the procedure described in Example 1, Step I. ¹ H NMR (200MHz, CDCl₃): δ 1.37 (s, 6H), 1.82 (m, 1H), 2.45-2.75 (m, 4H), 2.86 (m,1H), 4.49 (m, 1H), 5.05 (dd; 10, 6 Hz; 2H), 5.55 (s, 1H), 6.73 (s, 1H),6.96 (d, 4 Hz, 1H), 7.10-7.40 (m, 8H) and 8.68 (s, 1H). FAB-MS:calculated for C₂₃ H₂₇ N₃ O₄ 409; found 410 (M+H, 100%).

Step E:

2'- (t-Butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol, acetateester

To solution of 500 mg (1.60 mmol) of 2'-(t-butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol (Example 35,Step E) in 1 mL of dry methylene chloride under a nitrogen atmosphere atroom temperature was added by syringe 0.267 mL (1.91 mmol) oftriethylamine followed by 0.165 mL (1.76 mmol) of acetic anhydride. Thereaction mixture was stirred for 1 hour then diluted with 150 mL ofethyl acetate, washed with saturated aqueous ammonium chloride,saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride,dried over magnesium sulfate and filtered. The solvent was removed undervacuum to give 583 mg (>100%, containing a minor amount of ethylacetate) of the product as a white solid which was used in the next stepwithout further purification. ¹ H NMR (200 MHz, CDCl₃): δ 1.39 (s, 9H),2.10 (s, 3H), 4.22 (d, 6 Hz, 2H), 4.65 (s, 1H), 5.12 (s, 2H), 7.18-7.48(m, 8H). FAB-MS: calculated for C₂₁ H₂₅ NO₄ 355; found 356 (M+H).

Step F:

2'-Aminomethyl-1,1'-biphenyl-4-methanol, acetate ester, trifluoroacetate

Prepared from 2'-(t-butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol, acetate ester(Step E) according to the procedure described in Example 36, Step A. ¹ HNMR (200 MHz, CDCl₃): δ 2.03 (s, 3H), 3.98 (s, 2H), 5.07 (s, 2H),7.18-7.48 (m, 8H), 7.75 (s, 3H). FAB-MS: calculated for C₁₆ H₁₇ NO₂ 255;found 256 (M+H, 80%).

Step G:

2'- (Methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol, acetateester

Prepared from 2'-aminomethyl-1,1'-biphenyl-4-methanol, acetate ester,trifluoroacetate (Step F) according to the procedure described inExample 37, Step A. ¹ H NMR (200 MHz, CDCl₃): δ 2.10 (s, 3H), 2.65 (d,4.8 Hz, 3H), 4.27 (d, 4.8 Hz, 2H), 4.52 (m, 1H), 5.12 (s, 2H), 7.18-7.48(m, 8H). FAB-MS: calculated for C₁₈ H₂₀ N₂ O₃ 312; found 313 (M+H,100%).

Step H:

2'- (Methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol

To a solution of 498 mg (1.60 mmol) of 2'-(methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol, acetateester (Step G) in 10 mL of THFater (3:1) was added 335 mg (7.98 mmol) oflithium hydroxide monohydrate. After stirring at room temperature for 16hours the reaction mixture was diluted with 150 mL of ethyl acetate andwashed with brine (3×50 mL). The organic layer was dried over magnesiumsulfate, filtered and the solvent removed under vacuum to afford 411 mg(95%) of the product as a white solid. ¹ H NMR (200 MHz, CD₃ OD): δ 2.64(s, 3H), 4.20 (s, 2H), 4.62 (s, 2H), 7.12-7.45 (m, 8H). FAB-MS:calculated for C₁₆ H₁₈ N₂ O₂ 270; found 271 (M+H, 100%).

Step I:

2'- (Methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol,methanesulfonate ester

To solution of 100 mg (0.17 mmol) of 2'-(methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol (Step H) in5 mL of dry methylene chloride and 1 mL dry dimethylformamide under anitrogen atmosphere at 0° C. was added by syringe 0.077 mL (0.56 mmol)of triethylamine followed by 0.034 mL (0.44 mmol) of methanesulfonylchloride. The reaction mixture was stirred for 30 minutes at 0° C. thendiluted with 75 mL of methylene chloride, washed with water, saturatedaqueous sodium bicarbonate, saturated aqueous sodium chloride then driedover sodium sulfate and filtered. The solvent was removed under vacuumto give 128 mg (100%) of the product as a white solid which was used inthe next step without further purification. ¹ H NMR (200 MHz, CDCl₃): δ2.66 (d, 4 Hz, 3H), 2.97 (s, 3H), 4.26 (d, 5 Hz, 2H), 4.42 (m, 1H), 5.26(s, 2H), 7.18-7.48 (m, 8H). FAB-MS: calculated for C₁₇ H₂₀ N₂ O₄ S 348;found 349 (M+H, 100%).

Step J:

3-Benzyloxycarbonylamino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide

Prepared from 3-benzyloxycarbonylamino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide (Step D) and2'- (methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol,methanesulfonate ester (Step I) according to the procedure described inExample 35, Step H. ¹ H NMR (200 MHz, CDCl₃): δ 1.33 (s,6H), 1.78 (m,1H), 2.37-2.63 (m, 3H), 2.60 (d, 5 Hz, 3H), 4.20 (d, 6 Hz, 2H), 4.52 (m,2H), 4.72 (t, 6 Hz, 1H), 4.86 (d, 16 Hz, 1H), 4.89 (s, 2H), 5.10 (d, 15Hz, 1H), 5.69 (s, 1H), 6.73 (d, 7.5 Hz, 1H), 7.08-7.35 (m, 16H) 7.40 (m,1H). FAB-MS: calculated for C₃₉ H₄₃ N₅ O₅ 661; found 662 (M+H, 40%).

Step K:

3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate

The title compound was prepared from 3-benzyloxycarbonylamino-3-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide (StepJ) according to the procedure described in Example 36, Step C. ¹ H NMR(200 MHz, CD₃ OD): δ 1.32 (s, 3H), 1.35 (s, 3H), 2.0-2.35 (m, 2H),2.40-2.62 (m, 4H), 2.65 (s, 3H), 4.14 (dd; 17, 15 Hz; 2H), 4.40 (dd; 12,8 Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.21 (d, 15 Hz, 1H), 7.10-7.41 (m, 12H).FAB-MS: calculated for C₃₁ H₃₇ N₅ O₃ 527; found 528 (M+H, 100%).

EXAMPLE 49 3- 2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate

Step A:

3-Amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!-butanamide,trifluoroacetate

To a solution of 150 mg (0.40 mmol) of 3-t-butoxycarbonylamino-3-methyl-N- 2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide (Example 1,Step I) in 2 mL of methylene chloride at 0° C. was added 2 mL oftrifluoroacetic acid and the mixture stirred at room temperature for 1hour. All volatiles were removed under vacuum to give 130 mg (0.33 mmol,84%) of the product. ¹ H NMR (200 MHz, CD₃ OD): δ 1.33 (s, 3H), 1.37 (s,3H), 2.12 (m, 1H), 2.3-2.6 (m, 3H), 2.6-3.0 (m, 2H), 4.37 (dd; 8, 12 Hz;1H), 7.02 (d, 8 Hz, 1H), 7.1-7.3 (m, 3H). FAB-MS: calculated for C₁₅ H₂₁N₃ O₂ 275; found 276 (M+H, 100%).

Step B:

3- 2(R)-Benzyloxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate

To a solution of 1.0 g (2.6 mmol) of 3-amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate (Step A) in 25 mL of dry methanol was added 3.0 g ofdry 3 Å powdered molecular sieves followed by a solution of 2.5 g (17mmol) of (R)-2-benzyloxypropanol (prepared from methyl D-lactateaccording to the procedure of Hanessian and Kloss, Tetrahedron Lett.,26, 1261-1264 (1985).) in 5 mL of dry methanol. The pH of the mixturewas carefully adjusted to 6 by the addition of trifluoroacetic acid. Thereaction was stirred for 2 hours at room temperature at which time 15.4mL (15.4 mmol) of a 1.0 M solution of sodium cyanoborohydride intetrahydrofuran was added by syringe. The reaction was stirred for 72hours then filtered through a pad of Celite. To the filtrate was added 5mL of trifluoroacetic acid (CAUTION| evolution of hydrogen cyanide) andthe resulting mixture was stirred for three hours. The solvent wasremoved under vacuum to afford a clear oil which was purified by reversephase medium pressure liquid chromatography on C-8, eluting withmethanolB 0.1% aqueous trifluoroacetic acid (60:40), to afford 1.27 g(2.36 mmol, 92%) of the product as a white solid. ¹ H NMR (200 MHz, CD₃OD): δ 1.31 (d, 6 Hz, 3H), 1.40 (s, 3H), 1.43 (s, 3H), 2.17 (m, 1H),2.30 (m, 1H), 2.6-3.1 (m, 5H), 3.22 (dd; 3, 12 Hz; 1H), 3.86 (m, 1H),4.48 (dd; J, 12 Hz; 1H), 4.50 (d, 12 Hz, 1H), 4.70 (d, 12 Hz, 1H), 7.11(d, 8 Hz, 1H), 7.15-7.45 (m, 8H). FAB-MS: calculated for C₂₅ H₃₃ N₃ O₃423; found 424 (M+H, 100%).

Step C:

3- 2(R)-Benzyloxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide

To a solution of 2.034 g (3.788 mmol) of the intermediate obtained inStep B in 40 mL of methylene chloride was added 40 mL of water. Themixture was stirred vigorously while sufficient solid potassiumcarbonate was added to adjust the pH of the aqueous layer to 10-11.Stirring was discontinued and the layers allowed to separate. Theorganic layer was removed and the aqueous layer extracted twice morewith methylene chloride. The combined extracts were dried over potassiumcarbonate, filtered and solvents removed under vacuum to afford 1.53 g(3.62 mmol, 95%) of the product as a white solid.

Step D:

3- 2(R)-Benzyloxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide

Prepared from 3- 2(R)-benzyloxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide (Step C) and2'- (methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol,methanesulfonate ester (Example 48, Step I) according to the proceduredescribed in Example 35, Step H. ¹ H NMR (200 MHz, CD₃ OD): δ 1.10 (s,3H), 1.12 (s, 3H), 1.18 (d, 6 Hz, 3H), 1.95 (m, 1H), 2.12-2.39 (m, 3H),2.40-2.63 (m, 3H), 2.63 (s, 3H), 3.70 (m, 1H), 4.13 (s, 2H), 4.42 (dd;12, 8 Hz; 1H), 4.46 (d, 12 Hz, 1H), 4.59 (d, 12 Hz, 1H), 4.93 (d, 15 Hz,1H), 5.23 (d, 15 Hz, 1H), 7.02-7.40 (m, 17H). FAB-MS: calculated for C₄₁H₄₉ N₅ O₄ 675; found 676 (M+H, 100%).

Step E:

3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate

To a solution of 233 mg (0.345 mmol) of 3-2(R)-benzyloxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide (StepD) in 5 mL methanol was added 5 drops of concentrated hydrochloric acid.The resulting mixture was hydrogenated at ambient temperature over 50 mgof 30% palladium on carbon catalyst at 50 psi for 24 hours. The mixturewas filtered through Celite. To the filtrate was added 3 drops oftrifluoroacetic acid and the solvent was removed under vacuum to give asolid which was purified by reverse phase medium pressure liquidchromatography on C-8, eluting with methanolB 0.1% aqueoustrifluoroacetic acid (55:45), to afford 157 mg (65%) of the titlecompound as a white solid. ¹ H NMR (200 MHz, CD₃ OD): δ 1.18 (d, 6 Hz,3H), 1.34 (s, 3H), 1.36 (s, 3H), 2.02-2.22 (m, 1H), 2.22-2.43 (m, 1H),2.48-2.65 (m, 5H), 2.65 (s, 3H), 2.78 (m, 1H), 3.90 (m, 1H), 4.16 (s,2H), 4.38 (dd; 12, 8 Hz; 1H), 5.03 (d, 15 Hz, 1H), 5.17 (d, 15 Hz, 1H),7.10-7.40 (m, 12H). FAB-MS: calculated for C₃₄ H₄₃ N₅ O₄ 585; found586(M+H, 40%).

EXAMPLE 50 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate

Step A:

3-Amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide

To a solution of 502 mg (1.34 mmol) of 3-t-butoxycarbonylamino-3-methyl-N- 2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide (Example 1,Step I) in 3 mL of methylene chloride at 0° C. was added 0.160 mL (1.47mmol) of anisole followed by 3 mL of trifluoroacetic acid. The mixturestirred at room temperature for 3 hours. All volatiles were removedunder vacuum to give an oil which was dissolved in 10 mL of water. Tothis solution was added 268 mg (6.7 mmol) of sodium hydroxide and theresulting mixture was stirred until all the solids were dissolved. Thesolution was transferred to a separatory funnel and the aqueous layerwas extracted with chloroform (3×50 mL). The combined organic extractswere washed with brine, dried over sodium surf ate and filtered. Thesolvent was removed under vacuum to afford 368 mg (100%) of the productas a white solid. ¹ H NMR (200 MHz, CDCl₃): δ 1.27 (s, 6H), 1.95-2.30(m, 2H), 2.37-2.75 (m, 3H), 2.80-3.02 (m, 1H), 3.48 (s, 2H), 4.52 (m,1H), 6.97 (m, 1H), 7.1-7.27 (m, 3H), 7.98 (s, 1H), 8.29 (d, 7 Hz, 1H).FAB-MS: calculated for C₁₅ H₂₁ N₃ O₂ 275; found 276 (M+H, 100%).

Step B:

3- 2,2-Dimethyl-1,3-dioxolan-4(S)-yl!methyl!amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide

To a solution of 368 mg (1.34 mmol) of 3-amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide (Step A) in 10mL of dry methanol was added 1.5 g of dry 4 Å powdered molecular sievesfollowed by a solution of 520 mg (4.0 mmol) of D-glyceraldehydeacetonide (used crude as prepared according to the procedure of L. W.Hertel, C. S. Grossman and J. S. Kroin, Syn. Comm. 1991, 21, 151-154.)in 5 mL of dry methanol. The pH of the mixture was carefully adjusted to6 by the addition of 3 drops of acetic acid. The reaction was stirredfor 5 hours at room temperature at which time 4.0 mL (4.0 mmol) of a 1.0M solution of sodium cyanoborohydride in tetrahydrofuran was added bysyringe. The reaction was stirred for 16 hours then filtered through apad of Celite. The solvent was removed under vacuum to afford a clearoil which was purified by flash column chromatography on silica geleluting with chloroformB 10% aqueous ammonium hydroxide (33%) inmethanol (92:8) to afford 387 mg (78%) of the product as a white solid.¹ H NMR (200 MHz, CD₃ OD): δ 1.10 (s, 6H), 1.28 (s, 3H), 1.34 (s, 3H),2.08 (m, 1H), 2.26 (dd; 16, 15 Hz; 2H), 2.44 (m, 1H), 2.58-2.75 (m, 3H),2.87 (m, 1H), 3.63 (dd; 8, 7 Hz; 1H), 4.05 (dd; 8, 7 Hz; 1H), 4.20 (m,1H), 4.38 (dd; 12, 8 Hz; 1H), 4.84 (s, 1H), 7.00-7.40 (m, 4H). FAB-MS:calculated for C₂₁ H₃₁ N₃ O₄ 389; found 390 (M+H, 100%).

Step C:

3- 2,2-Dimethyl-1,3-dioxolan-4(S)-yl!methyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide

Prepared from 3-2,2-dimethyl-1,3-dioxolan-4(S)-yl!methyl!amino-3-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!butanamide (Step B) and2'- (methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol,methanesulfonate ester (Example 48, Step I) according to the proceduredescribed in Example 35, Step H.¹ H NMR (200 MHz, CD₃ OD): δ 1.14 (s,6H), 1.28 (s, 3H), 1.34 (s, 3H), 2.07 (m, 1H), 2.20-2.42 (m, 3H),2.48-2.76 (m, 4H), 2.64 (s, 3H), 3.64 dd; 8, 6 Hz; 1H), 4.05 (dd; 8, 6Hz; 1H), 4.14 (s, 2H), 4.20 (m, 1H), 4.40 (dd; 12, 8 Hz; 1H), 4.94 (d,15 Hz, 1H), 5.27 (d, 15 Hz, 1H), 7.10-7.40 (m, 12H). FAB-MS: calculatedfor C₃₇ H₄₆ N₅ O₅ 641; found 642 (M+H, 80%).

Step D:

3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methyl-amino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide,trifluoroacetate

To a solution of 137 mg (0.213 mmol) of 3-2,2-dimethyl-1,3-dioxolan-4(S)-yl!methyl!amino-3-methyl- N-2,3,4,5-tetrahydro-1- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide (StepC) in 2 mL of methanol was added 2.0 mL of 50% aqueous trifluoroaceticacid. The resulting solution was stirred at room temperature for 3 hoursat which time the solvent was removed under vacuum to give a solid whichwas purified by reverse phase medium pressure liquid chromatography onC-8, eluting with methanolB 0.1% aqueous trifluoroacetic acid (55:45),to afford 108 mg (70%) of the title compound as a white solid. ¹ H NMR(200 MHz, CD₃ OD): δ 1.35 (s, 3H), 1.37 (s, 3H), 2.02-2.22 (m, 1H),2.22-2.43 (m, 1H), 2.50-2.70 (m,4H), 2.64 (s,3H), 2.94 (dd, 12, 9 Hz;1H), 3.17 (dd, 12, 3 Hz; 1H), 3.51 (m, 2H), 3.82 (m, 1H), 4.16 (s, 2H),4.38 (dd, 12, 8 Hz; 1H), 5.03 (d, 15 Hz, 1H), 5.14 (d, 15 Hz, 1H),7.10-7.40 (m, 12H). FAB-MS: calculated for C₃₄ H₄₃ N₅ O₅ 601; found 602(M+H, 40%).

EXAMPLE 51 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(cyclopropylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2-Benzyloxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(cyclopropylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,hydrochloride (Example 35, Step I) and cyclopropyl amine according tothe procedure described in Example 46, Step A. ¹ H NMR (200 MHz, CD₃OD): δ 0.39 (m, 2H), 0.61 (m, 2H), 1.38 (s, 6H), 1.82 (m, 1H), 2.18-2.58(m, 4H), 4.18 (s, 2H), 4.32 (m, 1H), 4.86 (d, 15 Hz, 1H), 5.00 (s, 2H),5.21 (d, 15 Hz, 1H), 7.10 (m, 1H), 7.14-7.40 (m, 16H). FAB-MS:calculated for C₄₀ H₄₃ N₅ O₅ 673; found 674 (M+H, 70%).

Step B:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(cyclopropylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-benzyloxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- (cyclopropylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step A) according to the procedure described in Example 36, Step C. ¹ HNMR (200 MHz, CD₃ OD): δ 0.39 (m, 2H), 0.62 (m, 2H), 1.53 (s, 3H), 1.62(s, 3H), 2.10-2.45 (m, 3H), 2.58 (m, 2H), 4.19 (s, 2H), 4.37 (m, 1H),4.98 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.08-7.40 (m, 12H). FAB-MS:calculated for C₃₂ H₃₇ N₅ O₃ 539; found 540 (M+H, 80%).

EXAMPLE 52 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!-3-bromo-1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Step A:

4-Methylphenyltrimethylstannane

To a solution of 546 g (2.74 mol) of trimethyltin chloride intetrahydrofuran (4 L) under nitrogen at -10° C. was added dropwise,maintaining the temperature below -5° C. over 4 hours, 4.14 L of 1.0 Mp-tolylmagnesium bromide in diethyl ether (4.14 mol, 1.5 eq.). Thesuspension was allowed to warm slowly to room temperature over 12 hoursthen saturated ammonium chloride solution (1 L) was added followed bysufficient water (approximately 1 L) to dissolve the precipitate. Thesolution was extracted with ether-hexane (1:1) (1×4 L, 3×2 L). Thecombined organic phases were washed with brine, dried over magnesiumsulfate and the solvents removed under vacuum. Purification by flashchromatography on silica gel eluting with hexanethyl acetate (95:5) gavea pale yellow oil containing white crystals of 4,4'-dimethylbiphenylwhich were removed by filtration to leave 698 g (100%) of product. ¹ HNMR (300 MHz, CDCl₃): δ 0.30 (s, 9H), 2.34 (s, 3H), 7.19 (d, 7.7 Hz,2H), 7.40 (d, 7.7 Hz, 2H).

Step B:

4'-Methyl-1,1'-biphenyl-2-nitrile

A solution of 2.00 g (11.0 mmol) of 2-bromobenzonitrile, 2.93 g (11.5mmol) of 4-methylphenyltrimethylstannane (Step A) and 0.385 g (0.550mmol) of bis-triphenylphosphine palladium (II) chloride in 50 mL of drydimethylformamide under nitrogen was heated at 100° C. for 5.5 hours.The reaction was cooled to room temperature, poured into 150 mL of waterand extracted with ether (3×150 mL). The combined ether extracts werewashed with water (4×100 mL) and brine (100 mL), dried over magnesiumsulfate, filtered and the solvents removed under vacuum. Purification byflash chromatography on silica gel, eluting with hexane/ether (85:15),afforded 1.69 g (80%) of the product contaminated with about 10% of2-methylbenzonitrile. ¹ H NMR (200 MHz, CDCl₃): δ 2.40 (s, 3H), 7.27 (d,7 Hz, 2H), 7.30-7.65 (m, 5H), 7.72 (d, 6 Hz, 1H). EI-MS: calculated forC₁₄ H₁₁ N 193; found 193 (M⁺, 100%).

Step C:

3'-Bromo-4'-methyl-1,1'-biphenyl-2-nitrile

A solution of 5.2 g (27 mmol) of 4'-methyl-1,1'-biphenyl-2-nitrile (StepB) in 60 mL of methylene chloride at 0° C. was treated with 6.7 g ofsilver trifluoroacetate (30 mmol). When all the silver trifluoroacetatewas dissolved, 1.6 mL of bromine was added dropwise (4.95 g, 31 mmol)with vigorous stirring. After two hours, the reaction mixture wasfiltered and the solid washed with methylene chloride. The combinedorganic layers were washed once with dilute (<1 N) aqueous sodiumhydroxide and once with brine. The organic layer was removed, dried overmagnesium sulfate, filtered and concentrated under vacuum. The residuewas purified by preparative high pressure liquid chromatography onsilica, eluting with 10% etherexane to give 3 g (41%) of product. ¹ HNMR (200 MHz, CDCl₃): δ 2.46 (s, 3H), 7.2-7.8 (m, 7H).

Step D:

3'-Bromo-4'-bromomethyl-1,1'-biphenyl-2-nitrile

A solution of 1.0 g (3.7 mmol) of3'-bromo-4'methyl-1,1'-biphenyl-2-nitrile (Step C) in 15 mL of carbontetrachloride under a nitrogen atmosphere was treated with 0.720 g (4.04mmol) of N-bromosuccinimide followed by 60 mg (0.37 mmol) ofazobisisobutyronitrile (AIBN). The reaction mixture was heated at refluxfor four hours, cooled to room temperature and filtered through Celite.The solvent was removed under vacuum and the residue was dissolved inmethylene chloride and treated with decolorizing carbon. The solids werefiltered through Celite and the solvent removed under vacuum. Theresulting solid was triturated with cold ether, filtered and air driedto afford 920 mg (71%) of the product as an off-white solid. ¹ H NMR(200 MHz, CDCl₃): δ 4.64 (s, 2H), 7.4-7.8 (m, 7H). EI-MS: calculated forC₁₄ H₉ Br₂ N 351; found 351 (M⁺, 20%); 271 (M-Br, 100%).

Step E:

3'-Bromo-4'-acetoxmethyl-1,1'-biphenyl-2-nitrile

To a solution of 662 mg (1.89 mmol) of3'-bromo-4'-bromomethyl-1,1'-biphenyl-2-nitrile (Step D) in 10 mL of drydimethyl formamide was added 925 mg (9.43 mmol) of potassium acetate.The reaction mixture was heated at 50° C. for 2 hours then diluted with100 mL of water. The mixture was extracted with ethyl acetate (3×100mL). The organic extracts were combined, washed with water (100 mL),saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). Thesolution was dried over magnesium sulfate, filtered and the solventremoved under vacuum to give an oil which was purified by flash columnchromatography on silica gel, eluting with hexanes/ethyl acetate(75:25), to afford 400 mg (64%) of the product as a white solid. ¹ H NMR(200 MHz, CDCl₃): δ 2.14 (s, 3H), 5.22 (s, 2H), 7.4-7.8 (m, 7H). EI-MS:calculated for C₁₆ H₁₂ BrNO₂ 329; found 329, 331 (M⁺, 7%); 270, 272(M-Br, 100%).

Step F:

3'-Bromo-4'-hydroxymethyl-1,1'-biphenyl-2-nitrile

Prepared from 3'-bromo-4'-acetoxymethyl-1,1'-biphenyl-2-nitrile (Step E)according to the procedure described in Example 48, Step H. ¹ H NMR (200MHz, CDCl₃): δ 2.04 (s, 1H), 4.79 (s, 2H), 7.35-7.8 (m, 7H). EI-MS:calculated for C₁₄ H₁₀ BrNO 287, 289; found 287, 289 (M⁺, 5%), 269, 271(M-H₂ O, 100%).

Step G:

3'-Bromo-4'-t-butyldiphenylsilyloxymethyl-1,1'-biphenyl-2-nitrile

To a solution of 670 mg (2.35 mmol) of3'-bromo-4'-hydroxymethyl-1,1'-biphenyl-2-nitrile (Step F) in 5 mL ofdry dimethylformamide under a nitrogen atmosphere was added 237 mg (3.49mmol) of imidazole. The reaction mixture was cooled to 0° C. and 0.73 mL(2.8 mmol) of t-butylchlorodiphenylsilane was added dropwise by syringeover 5 minutes. The resulting solution was stirred at 0° C. for 15minutes then at room temperature for 2 hours. The reaction mixture waspoured into 100 mL of water and extracted with ether (3×75 mL). Thecombined ether extracts were washed with water (75 mL), saturatedaqueous sodium bicarbonate (75 mL) and brine (75 mL). The organic layerwas dried over magnesium sulfate, filtered and the solvent removed undervacuum to give an oil which was purified by flash column chromatographyon silica gel, eluting with hexanes/ethyl acetate (9:1), to afford 1.24g (100%) of the product as a clear oil. ¹ H NMR (200 MHz, CDCl₃): δ 1.13(s, 3H), 4.80 (s, 2H), 7.30-7.50 (m, 9H), 7.55-7.80 (m, 7H), 7.86 (d, 8Hz, 1H). FAB-MS: calculated for C₃₀ H₂₈ BrNOSi 526; found 527, 528, 271(60%).

Step H:

2'-Aminomethyl-3-bromo-1,1'-biphenyl-4-methanol

To a solution of 136 mg (0.258 mmol) of3'-bromo-4'-t-butyldiphenylsilyloxymethyl-1,1'-biphenyl-2-nitrile (StepG) in 3 mL of dry methylene chloride under a nitrogen atmosphere wasadded 199 mg (0.775 mmol) of tetra-n-butylammonium borohydride. Thereaction mixture was heated at reflux for 8 hours, cooled to roomtemperature, poured into 25 mL of water and extracted with ethyl acetate(3×35 mL). The combined organic extracts were washed with water (25 mL),saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). Theorganic layer was dried over magnesium sulfate, filtered and the solventremoved under vacuum to give an oil which was dissolved in 3 mL oftetrahydrofuran and treated with 1 mL of 6 N aqueous hydrochloric acid.The resulting solution was heated at reflux for 4 hours, cooled in anice bath and quenched with 10 mL of 1 N aqueous sodium hydroxide. Themixture was extracted with ethyl acetate (3×35 mL). The organic extractswere washed with water (25 mL), saturated aqueous sodium bicarbonate (25mL) and brine (25 mL). The organic layer was dried over sodium sulfate,filtered and the solvent removed under vacuum to give an oil which waspurified by flash column chromatography on silica gel, eluting withchloroformB 10% ammonium hydroxide (33%) in methanol (9:1), to afford 43mg (57%) of the product as an off-white solid. ¹ H NMR (200 MHz, CD₃OD): δ 3.69 (s, 2H), 4.68 (s, 2H), 7.16 (dd; 7, 6 Hz; 1H), 7.21-7.41 (m,4H), 7.47 (dd; 9, 8 Hz; 1H), 7.58 (d, 8 Hz, 1H). FAB-MS: calculated forC₁₄ H₁₄ BrNO 292; found 292, 293 (50%).

Step I:

2'- (Methylamino)carbonyl!amino!methyl-3-bromo-1,1'-biphenyl-4-methanol

To a solution of 68 mg (0.23 mmol) of2'-aminomethyl-3-bromo-1,1'-biphenyl-4-methanol (Step H) in 3 mL of drymethylene chloride and 1 mL of dry dimethylformamide under nitrogenatmosphere at 0° C. was added 0.015 mL (0.25 mmol) of methyl isocyanate.The reaction mixture was stirred for 30 minutes at 0° C. then dilutedwith 100 mL of ethyl acetate, washed with water, saturated aqueoussodium bicarbonate, saturated aqueous sodium chloride, dried overmagnesium sulfate and filtered. The solvent was removed under vacuum togive 71 mg (88%) of the product as a white solid which was used in thenext step without further purification. ¹ H NMR (200 MHz, CD₃ OD): δ2.64 (s, 3H), 4.20 (s, 2H), 4.69 (s, 2H), 7.16 (m, 1H), 7.22-7.43 (m,4H), 7.50 (d, 2 Hz, 1H), 7.58 (d, 8 Hz, 1H). FAB-MS: calculated for C₁₆H₁₇ BrN₂ O₂ 349; found 349, 351 (80%).

Step J:

2'- (Methylamino)carbonyl!amino!methyl-3-bromo-1,1'-biphenyl-4-methanol,methanesulfonate ester

Prepared from 2'-(methylamino)carbonyl!amino!methyl-3-bromo-1,1'-biphenyl-4-methanol(Step I) according to the procedure described in Example 48, Step I.FAB-MS: calculated for C₁₇ H₁₉ BrN₂ O₄ S 427; found 427,429 (40%).

Step K:

2-t-Butoxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from N-t-butoxycarbonyl-2-methylalanine and3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E)substituting benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate forbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateaccording to the procedure described in Example 1, Step I. ¹ H NMR (200MHz, CDCl₃): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m,3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H) and8.65 (s, 1H). FAB-MS: calculated for C₂₂ H₂₅ N₃ O₄ 395; found 396 (M+H,100%).

Step L:

2-t-Butoxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!-3-bromo1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-t-butoxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!propanamide (Step K) and2'- (methylamino)carbonyl!amino!methyl-3-bromo-1,1'-biphenyl-4-methanol,methanesulfonate ester (Step J) according to the procedure described inExample 35, Step H. ¹ H NMR (200 MHz, CDCl₃): δ 1.39 (s, 12H), 1.41 (s,3H), 1.92 (m, 1H), 2.48-2.75 (m, 6H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H),4.70 (m, 1H), 4.92 (m, 2H), 7.08-7.35 (m, 10H) 7.42 (m, 1H).

Step M:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!-3-bromo-1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

To a solution of 146 mg (0.211 mmol) of2-t-butoxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!-3-bromo-1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide (StepL) in 5 mL of methylene chloride was added 5 drops of anisole followedby 5 mL of trifluoroacetic acid. The reaction mixture was stirred atroom temperature for 1 hour then the solvent was removed under vacuum.The residue was purified by reverse phase medium pressure liquidchromatography on C-8, eluting with methanolB 0.1% aqueoustrifluoroacetic acid (60:40), to afford 87 mg (58%) of the titlecompound as a white solid. ¹ H NMR (200 MHz, CD₃ OD): δ 1.52 (s, 3H),1.59 (s, 3H), 2.32 (m, 2H), 2.60-3.02 (m, 2H), 2.65 (s, 3H), 4.17 (dd;18, 14 Hz; 2H), 4.43 (dd; 12, 9 Hz; 1H), 4.90 (d, 16 Hz, 1H), 5.34 (d,16 Hz, 1H), 7.10-7.42 (m, 8H), 7.50 (m, 3H). FAB-MS: calculated for C₃₀H₃₄ BrN₅ O₃ 592; found 593, 595 (100%).

EXAMPLE 53 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'- 2-methylaminocarbonyl!amino!ethyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

2'-(2-cyanoethyl)-1,1'-biphenyl-4-methanol, t-butyldiphenylsilyl ether

To a solution of 1.50 g (3.84 mmol) of4-(t-butyldiphenylsilyoxymethyl)phenylboronic acid (Example 35, Step C)in 8 mL of dry dimethylformamide was added 220 mg (0.19 mmol) oftetrakis(triphenylphosphine)palladium, 1.2 g (5.8 mmol) of tripotassiumphosphate and 0.791 g (4.03 mmol) of 2-bromophenylacetonitrile. Theresulting mixture was heated under nitrogen at 100° C. for 3 hours thencooled to room temperature. The reaction mixture was diluted with 100 mLof saturated aqueous ammonium chloride, transferred to a separatoryfunnel and extracted with ether (3×150 mL). The combined ether extractswere washed with saturated aqueous sodium bicarbonate (100 mL) andsaturated aqueous sodium chloride (100 mL), dried over magnesium sulfateand filtered. The solvent was removed under vacuum to give a crudeproduct which was purified by flash column chromatography on silica geleluting with hexanesthyl acetate (9:1) to afford 1.3 g (73%) of theproduct as a clear oil. ¹ H NMR (200 MHz, CDCl₃): δ 1.10 (s, 9H), 3.82(s, 2H), 4.82 (s, 2H), 7.18-7.47 (m, 11H), 7.50-7.62 (m, 3H), 7.73 (m,4H). FAB-MS: calculated for C₃₁ H₃₁ NOSi 461; found 462 (M+H, 20%).

Step B:

2'-(2-Cyanoethyl)-1,1'-biphenyl-4-methanol

Prepared from 2'-(2-cyanoethyl)-1,1'-biphenyl-4-methanol,t-butyldiphenylsilyl ether (Step A) according to the procedure describedin Example 35, Step F. ¹ H NMR (200 MHz, CDCl₃): δ 1.93 (s, 1H), 3.60(s, 2H), 4.73 (d, 4 Hz, 2H), 7.27 (m, 3H), 7.33-7.63 (m, 5H). FAB-MS:calculated for C₁₅ H₁₃ NO 223; found 222 (M-H), 205 (M-H₂ O, 100%).

Step C:

2'-(2-Cyanoethyl)-1,1'-biphenyl-4-methanol, t-butyldimethylsilyl ether

Prepared from 2'-(2-cyanoethyl)-1,1'-biphenyl-4-methanol (Step B)substituting t-butyldimethylsilyl chloride fort-butylchlorodiphenylsilane according to the procedure described inExample 52, Step G. ¹ H NMR (200 MHz, CDCl₃): δ 0.94 (s, 9H), 3.60 (s,2H), 4.77 (s, 2H), 7.24 (m, 3H), 7.40 (m, 4H), 7.52 (m, 1H). FAB-MS:calculated for C₂₁ H₂₇ NOSi 337; found 336 (M-H, 10%), 206 (100%).

Step D:

2'-(2-Aminoethyl)-1,1'-biphenyl-4-methanol

Prepared from 2'-(2-cyanoethyl)-1,1'-biphenyl-4-methanol,t-butyldimethylsilyl ether (Step C) according to the procedure describedin Example 52, Step H. ¹ H NMR (200 MHz, CD₃ OD): δ 2.63 (m, 2H), 2.75(m, 2H), 4.63 (s, 2H), 7.10-7.32 (m, 6H), 7.39 (d, 8 Hz, 2H). FAB-MS:calculated for C₁₅ H₁₇ NO 227; found 242 (M+2 Li, 100%).

Step E:

2'- 2- Methylaminocarbonyl!amino!ethyl-1,1'-biphenyl-4-methanol

Prepared from 2'-(2-aminoethyl)-1,1'-biphenyl-4-methanol (Step D)according to the procedure described in Example 52, Step I. ¹ H NMR (200MHz, CDCl₃): δ 2.56 (d, 5 Hz, 3H), 2.70 (t, 8 Hz, 2H), 2.89 (t, 5 Hz,1H), 3.10 (m, 2H), 4.37 (m, 1H), 4.52 (t, 6 Hz, 1H), 4.67 (d, 5 Hz, 2H),7.12-7.30 (m, 6H), 7.35 (d, 8 Hz, 1H). FAB-MS: calculated for C₁₇ H₂₀ N₂O₂ 284; found 285 (M+H, 100%).

Step F:

2'- 2- Methylaminocarbonyl!amino!ethyl-1,1'-biphenyl-4-methanol,methanesulfonate ester

Prepared from 2'- 2-methylaminocarbonyl!amino!ethyl-1,1'-biphenyl-4-methanol (Step E)according to the procedure described in Example 48, Step I.

Step G:

2-t-Butoxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'- 2-methylaminocarbonyl!amino!ethyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-t-butoxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl!propanamide (Example 52,Step K) and 2'- 2-methylaminocarbonyl!amino!ethyl-1,1'-biphenyl-4-methanol,methanesulfonate ester (Step F) according to the procedure described inExample 35, Step H. ¹ H NMR (200 MHz, CDCl₃): δ 1.39 (s, 12H), 1.41 (s,3H), 1.85 (m, 1H), 2.40-2.80 (m, 8H), 3.13 (m, 2H), 4.25 (m, 2H), 4.47(m, 1H), 4.94 (d, 16 Hz, 1H), 4.96 (s, 1H), 5.11 (d, 16 Hz, 1H),7.08-7.20 (m, 12H). FAB-MS: calculated for C₃₆ H₄₅ N₅ O₅ 627; found 628(M+H, 20%), 528 (100%).

Step H:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'- 2-methylaminocarbonyl!amino!ethyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-t-butoxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-1- 2'- 2- methylaminocarbonyl!amino!ethyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide(Step G) according to the procedure described in Example 52, Step M. ¹ HNMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.59(m, 5H), 2.67 (t, 7 Hz, 2H), 4.37 (dd; 12, 9 Hz; 1H), 4.96 (d, 15 Hz,1H), 5.21 (d, 15 Hz, 1H), 7.08-7.38 (m, 12H). FAB-MS: calculated for C₃₁H₃₇ N₅ O₃ 527; found 528 (M+H, 100%).

EXAMPLE 54 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)--yl!propanamide,trifluoroacetate

Step A:

2-t-Butoxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-4-oxo-5H-1,5-benzothiazepin-3(S)-yl!propanamide

Prepared from 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzothiazepin-4(5H)-one(prepared from D-cysteine (S-cysteine) and 2-fluoro-1-nitrobenzene bythe method of Slade, et al, J. Med. Chem., 28, 1517-1521 (1985)) andN-t-butoxycarbonyl-2-methylalanine by the procedure described in Example1, Step I. ¹ H NMR (200 MHz, CDCl₃): δ 1.22 (s, 15H), 2.86 (t, 12 Hz,1H), 3.85 (dd; 11, 7 Hz; 1H), 4.65 (m, 1H), 4.93 (s, 1H), 7.07 (dd; 8, 6Hz; 1H), 7.10-7.40 (m, 3H), 7.60 (dd; 8, 6 Hz; 1H), 8.0 (br s, 1H).FAB-MS: calculated for C₁₈ H₂₅ N₃ O₄ S 379; found 380 (M+H, 45%).

Step B:

2-t-Butoxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide

Prepared from 2-t-butoxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-4-oxo-5H-1,5-benzothiazepin-3(S)-yl!propanamide (StepA) and 2'- (methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol,methanesulfonate ester (Example 48, Step I) according to the proceduredescribed in Example 35, Step H. ¹ H NMR (200 MHz, CDCl₃): δ 1.34 (s,15H), 2.60 (d, 5 Hz, 3H), 2.78 (t, 12 Hz, 1H), 3.77 (dd; 11, 7 Hz; 1H),4.20 (d, 4 Hz, 2H), 4.62 (m, 1H), 4.93 (s, 1H), 4.98 (d, 16 Hz, 1H),5.15 (d, 16 Hz, 1H), 7.10-7.47 (m, 11H), 7.58 (dd; 8, 6 Hz; 1H). FAB-MS:calculated for C₃₄ H₄₁ N₅ O₅ S 631; found 632 (M+H, 20%).

Step C:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide

The title compound was prepared from 2-t-butoxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-5- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide(Step B) according to the procedure described in Example 52, Step M. ¹ HNMR (200 MHz, CD₃ OD): δ 1.52 (s, 3H), 1.59 (s, 3H), 2.64 (s, 3H), 3.17(t, 12 Hz, 1H), 3.56 (dd; 12, 8 Hz; 1H), 4.14 (s, 2H), 4.57 (dd; 12, 8Hz; 1H), 5.05 (d, 16 Hz, 1H), 5.20 (d, 16 Hz, 1H), 7.08-7.50 (m, 11H),7.62 (d, 7 Hz; 1H). FAB-MS: calculated for C₂₉ H₃₃ N₅ O₃ S 531; found532 (M+H, 100%).

EXAMPLE 55 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide,trifluoroacetate

Step A:

2-t-Butoxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-8-fluoro-4-oxo-5H-1,5-benzothiazepin-3(S)-yl!propanamide

Prepared from3(S)-amino-8-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepin-4(5H)-one(prepared from D-cysteine (S-cysteine) and 2,4-difluoro-1-nitrobenzeneby the method of Slade, et al, J. Med. Chem., 28, 1517-1521 (1985) usedfor the preparation of3(S)-amino-2,3,4,5-tetrahydro-1,5-benzothiazepin-4(5H)-one) andN-t-butoxycarbonyl-2-methylalanine by the procedure described in Example1, Step I. ¹ H NMR (200 MHz, CDCl₃): δ 1.42 (s, 15H), 2.90 (t, 12 Hz,1H), 3.83 (dd; 11, 7 Hz; 1H), 4.63 (m, 1H), 4.97 (s, 1H), 7.04 (m, 2H),7.31 (m, 2H), 8.33 (s, 1H). FAB-MS: calculated for C₁₈ H₂₅ FN₃ O₄ S 397;found 398 (M+H, 45%).

Step B:

2-t-Butoxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide

Prepared from 2-t-butoxycarbonylamino-2-methyl- N-2,3,4,5-tetrahydro-8-fluoro-4-oxo-5H-1,5-benzothiazepin-3(S)-yl!propanamide(Step A) and 2'-(methylamino)carbonyl!amino!methyl-1,1'-biphenyl-4-methanol,methanesulfonate ester (Example 48, Step I) according to the proceduredescribed in Example 35, Step H. ¹ H NMR (200 MHz, CDCl₃): δ 1.39 (s,15H), 2.62 (d, 5 Hz, 3H), 2.80 (t, 12 Hz, 1H), 3.75 (dd; 11, 7 Hz; 1H),4.22 (d, 4 Hz, 2H), 4.48 (m, 1H), 4.68 (m, 1H), 4.92 (s, 1H), 4.96 (d,16 Hz, 1H), 5.08 (d, 16 Hz, 1H), 7.10-7.47 (m, 11H). FAB-MS: calculatedfor C₃₄ H₄₀ FN₅ O₅ S 649; found 650 (M+H, 15%).

Step C:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide,trifluoroacetate

The title compound was prepared from 2-t-butoxycarbonylamino-2-methyl-N- 2,3,4,5-tetrahydro-5- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-8-fluoro-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide(Step B) according to the procedure described in Example 52, Step M. ¹ HNMR (200 MHz, CD₃ OD): δ 1.53 (s, 3H), 1.60 (s, 3H), 2.64 (s, 3H), 3.19(t, 12 Hz, 1H), 3.59 (dd; 12, 8 Hz; 1H), 4.14 (s, 2H), 4.57 (dd; 12, 8Hz; 1H), 5.00 (d, 16 Hz, 1H), 5.22 (d, 16 Hz, 1H), 7.08-7.43 (m, 10H),7.59 (dd; 9, 5 Hz; 1H). FAB-MS: calculated for C₂₉ H₃₂ FN₅ O₃ S 549;found 550 (M+H, 60%).

EXAMPLE 56 2-Amino-2-methyl- N- 7-fluoro-2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,hydrochloride

Step A:

3(R)-amino-7-nitro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

To a solution of 440 mg (2.50 mmol) of3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E)in 5 mL of concentrated sulfuric acid at 0° C. was added 265 mg (2.63mmol) of potassium nitrate. The resulting yellow solution was stirredfor 30 minutes at then at room temperature for 24 hours. The reactionmixture was poured carefully into 100 g of ice and the pH of theresulting mixture was adjusted to 11 by the portionwise addition ofsodium carbonate. The mixture was transferred to a separatory funnel andextracted thoroughly with ethyl acetate (4×100 mL). The organic extractswere combined, washed with brine (100 mL), dried over sodium sulfate andfiltered. The solvent was removed under vacuum to afford 385 mg (70%) ofthe product as a yellow solid. ¹ H NMR (200 MHz, CDCl₃): δ 1.58 (s, 2H),1.98 (m, 1H), 2.47-2.70 (m, 1H), 2.72-3.05 (m, 2H), 3.40 (dd; 11, 8 Hz;1H), 7.07 (d, 8 Hz, 1H), 7.92 (s, 1H), and 8.10 (m, 1H). FAB-MS:calculated for C₁₀ H₁₁ N₃ O₃ 221; found 222 (M+H,100%).

Step B:

2-Benzyloxycarbonylamino-2-methyl- N-7-nitro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!propanamide

Prepared from N-carbobenzyloxy-2-methylalanine and3(R)-amino-7-nitro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A)substituting benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate forbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateaccording to the procedure described in Example 1, Step I. ¹ H NMR (400MHz, CDCl₃): δ 1.48 (s, 3H), 1.49 (s, 3H), 2.00 (m, 1H), 2.73 (m, 2H),2.92 (m, 1H), 4.45 (m, 1H), 5.07 (s, 2H), 5.30 (s, 1H), 7.05 (d, 8 Hz,1H), 7.30 (m, 6H), 8.06 (dd; 8, 6 Hz; 1H), 8.13 (d, 2.5 Hz, 1H), 8.35(s, 1H). FAB-MS: calculated for C₂₂ H₂₄ N₄ O₆ 424; found 425 (M+H,100%).

Step C:

2-Benzyloxycarbonylamino-2-methyl- N-7-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!propanamide

To a solution of 310 mg (0.73 mmol) 2-benzyloxycarbonylamino-2-methyl-N- 7-nitro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!propanamide(Step B) in 20 mL of methanol was added 78 mg (1.5 mmol) of ammoniumchloride followed by 669 mg (10.2 mmol) of zinc dust. The resultingmixture was heated at reflux for four hours. The solids were removed byfiltration through Celite. The filter pad was washed with 30 mL of hotmethanol. The filtrate was combined and the solvent was removed undervacuum. The residue was dissolved in 10 mL of 1 N aqueous hydrochloricacid and the solids were filtered away. To the resulting solution wasadded sufficient 5 N aqueous sodium hydroxide until the pH wasapproximately 12. The solution was extracted with ethyl acetate (3×50mL). The combined organic extracts were washed with water then brine,dried over magnesium sulfate and filtered. The solvent was removed undervacuum to afford 256 mg (85%) of the product as a white solid. ¹ H NMR(400 MHz, CDCl₃): δ 1.48 (s, 3H), 1.50 (s, 3H), 1.78 (m, 1H), 2.47 (m,1H), 2.71 (m, 1H), 2.82 (m, 1H), 3.67 (s, 2H), 4.44 (m, 1H), 5.05 (s,2H), 5.39 (s, 1H), 6.50 (m, 2H), 6.74 (d, 8 Hz, 1H), 7.04 (d, 7 Hz, 1H),7.32 (m, 6H). FAB-MS: calculated for C₂₂ H₂₆ N₄ O₄ 410; found 411 (M+H,100%).

Step D:

2-Amino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!-propanamide

To a solution of 256 mg (0.624 mmol) of2-benzyloxycarbonylamino-2-methyl- N-7-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!propanamide(Step C) in 1.2 mL of water was added 0.171 mL of concentratedhydrochloric acid. The resulting mixture was stirred until all thesolids were dissolved then the solution was cooled to 0° C. To thissolution was added a solution of 52 mg (0.75 mmol) of sodium nitrite ina minimal amount of water. After 30 minutes at 0° C., 0.156 mL (1.06mmol) of 60 weight percent aqueous hexafluorophosphoric acid was addeddropwise. Immediately a white precipitate formed. The solids werefiltered and washed with ice cold water, then air dried. The resultingsolid was dried under vacuum overnight.

The solid was slurried in 5 mL of mesitylene and the flask equipped witha nitrogen purge was placed in a 165° C. oil bath for 5 minutes. Rapidgas evolution was observed. The mixture was cooled to room temperatureand diluted with 100 mL of ethyl acetate. The resulting solution waswashed with sodium bicarbonate then brine, dried over magnesium sulfateand the solvent was removed under vacuum. The residue was purified byflash column chromatography on silica gel eluting with chloroformB 10%ammonium hydroxide (33%) in methanol to afford 33 mg (23%) of theproduct as an off-white solid. ¹ H NMR (200 MHz, CDCl₃): δ 1.30 (s, 6H),2.10 (m, 1H), 2.50 (m, 1H), 2.73 (m, 1H), 2.89 (m, 1H) 4.32 (dd; 12, 8Hz; 1H), 5.05 (s, 3H), 7.05 (m, 3H). FAB-MS: calculated for C₁₄ H₁₈ FN₃O₂ 279; found 280 (M+H, 100%).

Step E:

2-Benzyloxycarbonylamino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!propanamide

To a solution of 33 mg (0.12 mmol) of 2-amino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!propanamide(Step D) in 1 mL of methylene chloride was 32 mg (0.13 mmol) ofN-(benzyloxycarbonyloxy)succinimide. The solution was stirred at roomtemperature for 24 hours then quenched with 5 drops of 33% aqueousammonium hydroxide. The solvent was removed under vacuum and the residuewas purified by flash column chromatography on silica gel eluting withethyl acetateexanes (75:25) to afford 25 mg (46%) of the product as anoff-white solid. ¹ H NMR (400 MHz, CDCl₃): δ 1.48 (s, 3H), 1.50 (s, 3H),1.82 (m, 1H), 2.56 (m, 1H), 2.71 (m, 1H), 2.86 (m, 1H), 4.42 (m, 1H),5.05 (s, 2H), 5.43 (s, 1H), 6.90 (m, 2H), 7.09 (d, 8 Hz, 1H), 7.30 (m,5H), 8.09 (s, 1H). FAB-MS: calculated for C₂₂ H₂₄ FN₃ O₄ 413; found 414(M+H, 100%).

Step F:

2-Benzyloxycarbonylamino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1- 2'- (t-butoxycarbonylamino)methyl!1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl!propanamide(Step E) and 2'-(t-butoxycarbonylamino)methyl!-1,1'-biphenyl-4-methanol,methanesulfonate ester (Example 35, Step G) according to the proceduredescribed in Example 35, Step H. ¹ H NMR (200 MHz, CDCl₃): δ 1.39 (s,9H), 1.48 (s, 3H), 1.51 (s, 3H), 1.78 (m, 1H), 2.35-2.70 (m, 3H), 4.18(d, 7 Hz, 2H), 4.42 (m, 1H), 4.58 (m, 1H), 4.75 (d, 16 Hz, 1H), 5.05 (s,2H), 5.27 (d, 16 Hz, 1H), 5.35 (s, 1H), 6.88 (dd; 8, 6 Hz; 1H), 6.98 (m,1H), 7.09 (d, 6 Hz,1H), 7.14-7.35 (m, 13H), 7.40 (d, 8 HZ, 1H). FAB-MS:calculated for C₄₁ H₄₅ FN₄ O₆ 708; found 709 (M+H).

Step G:

2-Benzyloxycarbonylamino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1- 2'- (t-butoxycarbonylamino)methyl!1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide (Step F)according to the procedure described in Example 36, Step A. ¹ H NMR (200MHz, CDCl₃): δ 1.40 (s, 6H), 1.90 (m, 1H), 2.25-2.65 (m, 3H), 4.05 (s,2H), 4.35 (m, 1H), 4.78 (d, 16 Hz, 1H), 4.96 (s, 2H), 5.05 (d, 16 Hz,1H), 5.55 (s, 1H), 6.90 (m, 3H), 7.00-7.50 (m, 17H), 7.80 (s, 1H).FAB-MS: calculated for C₃₆ H₃₇ FN₄ O₄ 608; found 609 (M+H, 100%).

Step H:

2-Benzyloxycarbonylamino-2-methyl- N- 7-fluoro-2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from 2-benzyloxycarbonylamino-2-methyl- N-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1- 2'-(aminomethyl)1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate (Step G) and methyl isocyanate according to theprocedure described in Example 35, Step I. ¹ H NMR (400 MHz, CDCl₃): δ1.44 (s, 3H), 1.45 (s, 3H), 1.78 (m, 1H), 1.85 (s, 1H), 2.30-2.60(m,3H), 2.57 (d, 4 Hz, 3H), 4.18 (d, 5 Hz, 2H), 4.40 (m, 1H), 4.62 (m,1H), 4.80 (m, 2H), 5.00 (s, 2H), 5.17 (d, 15 Hz, 1H), 540 (s, 1H), 6.85(m, 1H), 6.96 (m, 1H), 7.08-7.35 (m, 13H), 7.39 (m, 1H). FAB-MS:calculated for C₃₈ H₄₀ FN₅ O₅ 665; found 666 (M+H, 100%).

Step I:

2-Amino-2-methyl- N- 7-fluoro-2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

2-Benzyloxycarbonylamino-2-methyl- N- 7-fluoro-2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!-amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide (30mg, 0.045 mmol) (Step H) was dissolved in 1 mL of 30% hydrobromic acidin acetic acid. The mixture was stirred at room temperature for 1 hour.The solvent was removed under vacuum to give a solid which was purifiedby reverse phase medium pressure liquid chromatography on C-8 elutingwith methanolB 0.1% aqueous trifluoroacetic acid (60:40) to afford 27 mg(93%) of the title compound as an off-white solid. ¹ H NMR (400 MHz, CD₃OD): δ 1.55 (s, 3H), 1.64 (s, 3H), 2.28 (m, 2H), 2.62 (m, 2H), 2.67 (s,3H), 4.16 (s, 2H), 4.39 (dd; 12, 8 Hz; 1H), 4.96 (d, 15 Hz, 1H), 5.25(d, 15 Hz, 1H), 7.01-7.19 (m, 3H), 7.20-7.39 (m, 6H), 7.40 (m, 2H).FAB-MS: calculated for C₃₀ H₃₄ FN₅ O₃ 531; found 532 (M+H, 100%).

EXAMPLE 57 3- 2(R)-Hydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-5- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide

Step A:

3- 2(R)-Benzyloxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide

Prepared from 2-amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide,trifluoroacetate (Example 54) and (R)-2-benzyloxypropanal (prepared frommethyl D-lactate according to the procedure of Hanessian and Kloss,Tetrahedron Lett., 26, 1261-1264 (1985) according to the proceduredescribed in Example 49, Step B.

Step B:

3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide

The title compound is prepared from 3-2(R)-benzyloxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide(Step A) by the procedure described in Example 49, Step E.

EXAMPLE 58 3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N-2,3,4,5-tetrahydro-5- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide

Step A:

3- 2,2-Dimethyl-1,3-dioxolan-4(S)-yl!methyl!amino-3-methyl- N-2,3,4,5-tetrahydro-5- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide

Prepared from 2-amino-2-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!propanamide,trifluoroacetate (Example 54) and D-glyceraldehyde acetonide (used crudeas prepared according to the procedure of Hertel, L. W.; Grossman, C.S.; Kroin, J. S. Syn. Comm., 1991, 21, 151-154) by the proceduredescribed in Example 50, Step B.

Step B:

3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-5- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide

The title compound is prepared from 3-2,2-dimethyl-1,3-dioxolan-4(S)-yl!methyl!amino-3-methyl- N-2,3,4,5-tetrahydro-5- 2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-4-oxo-1,5-benzothiazepin-3(S)-yl!butanamide(Step A) by the procedure described in Example 50, Step D.

EXAMPLE 59 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

3(R)-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one

To a suspension of 576 mg (3.27 mmol) of3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B)in 5 mL methylene chloride at room temperature was added 0.46 mL (334mg, 3.3 mmol, 1.0 eq.) of triethylamine followed by 0.75 mL (712 mg,3.27 mmol, 1.1 eq) of di-t-butyldicarbonate. The mixture was stirred for4 hours at room temperature then added to 50 mL of ethyl acetate andwashed with 5% aqueous citric acid (3×), saturated aqueous sodiumbicarbonate and saturated aqueous sodium chloride. The organic layer wasremoved, dried over magnesium sulfate, filtered and solvents removedunder vacuum to give 884 mg (3.20 mmol, 98%) of th product as a whitesolid. ¹ H NMR (200 MHz, CDCl₃): δ 1.40 (s, 9H), 2.00 (m, 1H), 2.65 (m,2H), 2.95 (m, 1H), 4.29 (m, 1H), 5.42 (br d, 8 Hz, 1H), 6.97 (d, 7 Hz,1H), 7.2 (m, 3H), 7.50 (br s, 1H).

Step B:

3(R)-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- 2'-cyano1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-2-one

Prepared from 4'-bromomethyl-1,1'-biphenyl-2-nitrile (prepared by themethod of M. Fisher, et al, U.S. Pat. No. 5,206,235) and3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one(Step A) by the procedure described in Example 1, Step Q. ¹ H NMR (400MHz, CDCl₃): δ 1.39 (s, 9H), 1.90 (m, 1H), 2.40-2.60 (m, 3H), 4.28 (m,1H), 4.94 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 5.43 (d, 7 Hz, 1H),7.1-7.3 (m, 4H), 7.33 (d, 8 Hz, 2H), 7.35-7.50 (m, 4H), 7.60 (t, 8 Hz,1H), 7.72 (d, 8 Hz, 1H). FAB-MS: calculated for C₂₉ H₂₉ N₃ O₃ 467; found468 (M+H, 15%), 368 (M-BOC, 100%).

Step C:

3(R)-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- 2'-aminomethyl1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-2-one

To a solution of 200 mg (0.43 mmol) of the intermediate obtained in StepB in 5 mL of ethanol was added 5 mL of liquid ammonia and the resultingmixture hydrogenated at 200-400 psi and 80° C. for 6 hours over 60 mg ofRaney nickel. The reaction mixture was cautiously vented and allvolatiles removed by a steady stream of nitrogen. The residue wasredissolved in chloroform, filtered through Celite and the filtrateconcentrated under vacuum to give 149 mg (0.32 mmol, 74%) of the productas a white foam which was used without purification.

Step D:

3(R)-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-2-one

A solution of 31 mg (0.066 mmol) of the intermediate obtained in Step Cin I mL of methylene chloride at room temperature was treated with 1drop of triethylamine followed by 5 μL (6 mg, 0.067 mmol, 1 eq.) ofmethyl chloroformate. The mixture was stirred at room temperature for 1hour then diluted into 10 mL of ethyl acetate and washed with 5% aqueouscitric acid and saturated aqueous sodium chloride. The organic layer wasremoved, dried over magnesium sulfate, filtered and solvents removedunder vacuum. The residue was purified by medium pressure liquidchromatography on silica, eluting with 5% methanol in ethyl acetate, togive 33 mg (0.062 mmol, 95%) of the product as a colorless glass. ¹ HNMR (400 MHz, CDCl₃): δ 1.38 (s, 9H), 1.91 (m, 1H), 2.43-2.60 (m, 3H),3.62 (s, 3H), 4.26 (m, 3H), 4.68 (br t, 1H), 4.93 (d, 15 Hz, 1H), 5.18(d, 15 Hz, 1H), 5.45 (br d, 7 Hz, 1H), 7.13-7.35 (m, 11H), 7.41 (d, 8Hz, 1H). FAB-MS: calculated for C₃₁ H₃₅ N₃ O₅ 529; found 530 (M+H, 25%),430 (M-BOC, 100%).

Step E:

2-t-Butoxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

A solution of 33 mg (0.062 mmol) of the intermediate obtained in Step Din 2 mL of methanol at room temperature was treated with 0.5 mL ofconcentrated hydrochloric acid. After 2 hours, solvents were removedunder vacuum and the residue further dried under high vacuum for 1 hour.

The amine hydrochloride obtained above was taken up in 1 mL of methylenechloride and treated with 13 mg (0.064 mmol, 1.03 eq.) ofN-t-butoxycarbonyl-α-methylalanine, 26 μL of triethylamine (19 mg, 0.19mmol, 3 eq.) and finally, 49 mg (0.094 mmol, 1.5 eq.) ofbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. Afterstirring at room temperature for 1 hour, the reaction mixture wasdiluted into 10 mL of ethyl acetate and washed with 5% aqueous citricacid, saturated aqueous sodium bicarbonate and saturated aqueous sodiumchloride. The organic layer was removed, dried over magnesium sulfate,filtered and solvents removed under vacuum. The residue was purified bymedium pressure liquid chromatography on silica, eluting with ethylacetate, to give 37 mg (0.060 mmol, 96%) of the product as a clearglass. ¹ H NMR (400 MHz, CDCl₃): δ 1.41 (s, 9H), 1.42 (s, 3H), 1.44 (s,3H), 1.84 (m, 1H), 2.40-2.65 (m, 3H), 3.61 (s, 3H), 4.24 (d, 6 Hz, 2H),4.48 (m, 1H), 4.68 (br t, 1H), 4.89 (d, 15 Hz, 1H), 4.91 (br s, 1H),5.20 (d, 15 Hz, 1H), 7.15-7.35 (m, 11H), 7.40 (d, 8 Hz, 1H). FAB-MS:calculated for C₃₅ H₄₂ N₄ O₆ 614; found 615 (M+H, 5%), 515 (M-BOC,100%).

Step E:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

A solution of 35 mg (0.057 mmol) of the intermediate obtained in Step Ein 1 mL of methanol at room temperature was treated with 0.5 mL ofconcentrated hydrochloric acid. After 3 hours, solvents were removedunder vacuum and the residue purified by medium pressure liquidchromatography on C8, eluting with methanolB 0.1% aqueoustrifluoroacetic acid (65:35), to give 35 mg (0.055 mmol, 98%) of thetitle compound as a colorless glass. ¹ H NMR (400 MHz, CD₃ OD): δ 1.55(s, 3H), 1.64 (s, 3H), 2.27 (m, 2H), 2.61 (m, 2H), 3.60 (s, 3H), 4.14(s, 2H), 4.40 (m, 1H), 5.02 (d, 15 Hz, 1H), 5.22 (d, 15 Hz, 1H), 7.14(d, 8 Hz, 1H), 7.20-7.40 (m, 11H), 8.22 (br d, 8 Hz, 1H). FAB-MS:calculated for C₃₀ H₃₄ N₄ O₄ 514; found 515 (M+H, 55%).

EXAMPLE 60 2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(benzyloxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,trifluoroacetate

Step A:

3(R)-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- 2'-(benzyloxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-2-one

A solution of 64 mg (0.14 mmol) of3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1- 2'-aminomethyl1,1'-biphenyl!-4-yl!methyl!-1H-benzazepin-2-one (Example 59, Step C) in1 mL of methylene chloride at room temperature was treated with 1 dropof triethylamine followed by 36 mg (0.14 mmol, 1 eq.) ofN-(benzyloxycarbonyloxy)succinimide and 5 mg of N-hydroxybenzotriazole.The mixture was stirred at room temperature for 1 hour then added to 10mL of ethyl acetate and washed with 5% aqueous citric acid, saturatedaqueous sodium bicarbonate and saturated aqueous sodium chloride. Theorganic layer was removed, dried over magnesium sulfate, filtered andsolvents removed under vacuum. The residue was purified by mediumpressure liquid chromatography on silica, eluting with ethylacetateexanes (2:1), to give 68 mg (0.11 mmol, 83%) of the product as awhite, crusty foam. ¹ H NMR (400 MHz, CDCl₃): δ 1.38 (s, 9H), 1.89 (m,1H), 2.40-2.60 (m, 3H), 4.27 (m, 3H), 4.75 (br t, 1H), 4.92 (d, 15 Hz,1H), 5.05 (s, 2H), 5.18 (d, 15 Hz, 1H), 5.44 (br d, 7 Hz, 1H), 7.10-7.35(m, 11H), 7.40 (d, 8 Hz, 1H). FAB-MS: calculated for C₃₇ H₃₉ N₃ O₅ 605;found 606 (M+H, 2%), 506 (M-BOC, 100%).

Step B:

2-t-Butoxycarbonylamino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(benzyloxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide

Prepared from the intermediate obtained in Step A andN-t-butoxycarbonyl-α-methylalanine by the procedure described in Example59, Step E. ¹ H NMR (400 MHz, CDCl₃): δ 1.41 (s, 9H), 1.42 (s, 3H), 1.44(s, 3H), 1.82 (m, 1H), 2.38-2.65 (m, 3H), 4.27 (d, 6 Hz, 2H), 4.47 (m,1H), 4.74 (br t, 1H), 4.87 (d, 15 Hz, 1H), 4.92 (br s, 1H), 5.05 (s,2H), 5.21 (d, 15 Hz, 1H), 7.10-7.35 (m, 11H), 7.40 (d, 8 Hz, 1H).FAB-MS: calculated for C₄₁ H₄₆ N₄ O₆ 690; found 691 (M+H, 3%), 591(M-BOC, 100%).

Step C:

2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(benzyloxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3-(R)-yl!propanamide,trifluoroacetate

The title compound was prepared from the intermediate obtained in Step Bby the procedure described in Example 59, Step F. ¹ H NMR (400 MHz, CD₃OD): δ 1.54 (s, 3H), 1.64 (s, 3H), 2.27 (m, 2H), 2.60 (m, 2H), 4.16 (s,2H), 4.39 (dd; 7, 11 Hz; 1H), 5.00 (d, 15 Hz, 1H), 5.05 (s, 2H), 5.22(d, 15 Hz, 1H), 7.14 (d, 8 Hz, 1H), 7.20-7.40 (m, 11H). FAB-MS:calculated for C₃₆ H₃₈ N₄ O₄ 590; found 591 (M+H, 100%).

EXAMPLE 61

Utilizing the procedures described in Examples 1 to 60 and generalmethods of organic synthesis described in the chemical literature andfamiliar to one skilled in the art, the following compounds of Formula Ican be prepared from the appropriately substituted starting materialsand reagents.

    __________________________________________________________________________     ##STR44##                                                                    R.sup.1                                                                             R.sup.9   A             R.sup.4      R.sup.5                            __________________________________________________________________________           ##STR45##                                                                               ##STR46##                                                                                   ##STR47##   H                                  H                                                                                    ##STR48##                                                                               ##STR49##    CH.sub.2 CH.sub.2 OH                                                                       H                                  H                                                                                    ##STR50##                                                                               ##STR51##                                                                                   ##STR52##   H                                  H                                                                                    ##STR53##                                                                               ##STR54##                                                                                   ##STR55##   H                                  H                                                                                    ##STR56##                                                                               ##STR57##                                                                                   ##STR58##   H                                  H                                                                                    ##STR59##                                                                               ##STR60##    CH.sub.2 CH.sub.2 CH.sub.3                                                                 H                                  H                                                                                    ##STR61##                                                                               ##STR62##                                                                                   ##STR63##   H                                  6-F                                                                                  ##STR64##                                                                               ##STR65##    H            H                                  7-F                                                                                  ##STR66##                                                                               ##STR67##    H            H                                  7-CF.sub.3                                                                           ##STR68##                                                                               ##STR69##    H            H                                  7-OCH.sub.3                                                                          ##STR70##                                                                               ##STR71##    H            H                                  7-OH                                                                                 ##STR72##                                                                               ##STR73##    H            H                                  7-SCH.sub.3                                                                          ##STR74##                                                                               ##STR75##    H            H                                  7-S(O)CH.sub.3                                                                       ##STR76##                                                                               ##STR77##    H            H                                  8-OCH.sub.3                                                                          ##STR78##                                                                               ##STR79##    H            H                                  8-F                                                                                  ##STR80##                                                                               ##STR81##    H            H                                  8-Cl                                                                                 ##STR82##                                                                               ##STR83##    H            H                                  8-I                                                                                  ##STR84##                                                                               ##STR85##    H            H                                  H                                                                                    ##STR86##                                                                               ##STR87##    H            H                                  H                                                                                    ##STR88##                                                                               ##STR89##    H            H                                  H                                                                                    ##STR90##                                                                               ##STR91##    H            H                                  H                                                                                    ##STR92##                                                                               ##STR93##    H            H                                  H                                                                                    ##STR94##                                                                               ##STR95##    H            H                                  H                                                                                    ##STR96##                                                                               ##STR97##    CH.sub.3     H                                  H                                                                                    ##STR98##                                                                               ##STR99##    H            H                                  H                                                                                    ##STR100##                                                                              ##STR101##   H            H                                  H                                                                                    ##STR102##                                                                              ##STR103##                                                                                  ##STR104##  H                                  H                                                                                    ##STR105##                                                                              ##STR106##                                                                                  ##STR107##  H                                  H                                                                                    ##STR108##                                                                              ##STR109##   H            H                                  H                                                                                    ##STR110##                                                                              ##STR111##   H            H                                  H                                                                                    ##STR112##                                                                              ##STR113##   H            H                                  H                                                                                    ##STR114##                                                                              ##STR115##   --           --                                 H                                                                                    ##STR116##                                                                              ##STR117##   --           --                                 H                                                                                    ##STR118##                                                                              ##STR119##   --           --                                 __________________________________________________________________________

EXAMPLE 62

Utilizing the procedures described in Examples 1 to 60 and generalmethods of organic synthesis described in the chemical literature andfamiliar to one skilled in the art, the following compounds of Formula Ican be prepared from the appropriately substituted starting materialsand reagents.

    __________________________________________________________________________     ##STR120##                                                                   R.sup.1                                                                           R.sup.9       A          R.sup.4                                          __________________________________________________________________________         ##STR121##                                                                                  ##STR122##                                                                              H                                                H                                                                                  ##STR123##                                                                                  ##STR124##                                                                              H                                                H                                                                                  ##STR125##                                                                                  ##STR126##                                                                               ##STR127##                                      H                                                                                  ##STR128##                                                                                  ##STR129##                                                                               ##STR130##                                      H                                                                                  ##STR131##                                                                                  ##STR132##                                                                               ##STR133##                                      H                                                                                  ##STR134##                                                                                  ##STR135##                                                                               ##STR136##                                      H                                                                                  ##STR137##                                                                                  ##STR138##                                                                               ##STR139##                                      7-F                                                                                ##STR140##                                                                                  ##STR141##                                                                               ##STR142##                                      7-CF.sub.3                                                                         ##STR143##                                                                                  ##STR144##                                                                               ##STR145##                                      7-OCH.sub.3                                                                        ##STR146##                                                                                  ##STR147##                                                                               ##STR148##                                      7-SCH.sub.3                                                                        ##STR149##                                                                                  ##STR150##                                                                               ##STR151##                                      7-F                                                                                ##STR152##                                                                                  ##STR153##                                                                              H                                                7-F                                                                                ##STR154##                                                                                  ##STR155##                                                                              H                                                7-F                                                                                ##STR156##                                                                                  ##STR157##                                                                              H                                                7-F                                                                                ##STR158##                                                                                  ##STR159##                                                                              H                                                7-F                                                                                ##STR160##                                                                                  ##STR161##                                                                               ##STR162##                                      7-CF.sub.3                                                                         ##STR163##                                                                                  ##STR164##                                                                               ##STR165##                                      6-F                                                                                ##STR166##                                                                                  ##STR167##                                                                               ##STR168##                                      __________________________________________________________________________

EXAMPLE 63

Utilizing the procedures described in Examples 1 to 60 and generalmethods of organic synthesis described in the chemical literature andfamiliar to one skilled in the art, the following compounds of Formula Ican be prepared from the appropriately substituted starting materialsand reagents.

    __________________________________________________________________________     ##STR169##                                                                   X   n p R.sup.9    A         R.sup.4                                          __________________________________________________________________________    --  0 3                                                                                ##STR170##                                                                               ##STR171##                                                                             H                                                --  0 3                                                                                ##STR172##                                                                               ##STR173##                                                                              ##STR174##                                      --  0 1                                                                                ##STR175##                                                                               ##STR176##                                                                             H                                                --  0 1                                                                                ##STR177##                                                                               ##STR178##                                                                              ##STR179##                                      --  0 0                                                                                ##STR180##                                                                               ##STR181##                                                                             H                                                --  0 0                                                                                ##STR182##                                                                               ##STR183##                                                                              ##STR184##                                      CO  1 1                                                                                ##STR185##                                                                               ##STR186##                                                                              ##STR187##                                      CHOH                                                                              1 1                                                                                ##STR188##                                                                               ##STR189##                                                                              ##STR190##                                      S   1 0                                                                                ##STR191##                                                                               ##STR192##                                                                             H                                                S   1 0                                                                                ##STR193##                                                                               ##STR194##                                                                             H                                                S   1 0                                                                                ##STR195##                                                                               ##STR196##                                                                              ##STR197##                                      SO  1 0                                                                                ##STR198##                                                                               ##STR199##                                                                             H                                                SO  1 0                                                                                ##STR200##                                                                               ##STR201##                                                                             H                                                SO  1 0                                                                                ##STR202##                                                                               ##STR203##                                                                              ##STR204##                                      SO  1 0                                                                                ##STR205##                                                                               ##STR206##                                                                              ##STR207##                                      S   1 2                                                                                ##STR208##                                                                               ##STR209##                                                                             H                                                S   1 2                                                                                ##STR210##                                                                               ##STR211##                                                                             H                                                S   1 2                                                                                ##STR212##                                                                               ##STR213##                                                                              ##STR214##                                      S   1 2                                                                                ##STR215##                                                                               ##STR216##                                                                              ##STR217##                                      S   1 2                                                                                ##STR218##                                                                               ##STR219##                                                                             H                                                S   1 2                                                                                ##STR220##                                                                               ##STR221##                                                                             H                                                S   1 2                                                                                ##STR222##                                                                               ##STR223##                                                                              ##STR224##                                      S   1 2                                                                                ##STR225##                                                                               ##STR226##                                                                              ##STR227##                                      O   1 1                                                                                ##STR228##                                                                               ##STR229##                                                                             H                                                O   1 1                                                                                ##STR230##                                                                               ##STR231##                                                                             H                                                O   1 1                                                                                ##STR232##                                                                               ##STR233##                                                                              ##STR234##                                      O   1 1                                                                                ##STR235##                                                                               ##STR236##                                                                              ##STR237##                                      __________________________________________________________________________

EXAMPLE 64

Utilizing the procedures described in Examples 1 to 60 and generalmethods of organic synthesis described in the chemical literature andfamiliar to one skilled in the art, the following compounds of Formula Ican be prepared from the appropriately substituted starting materialsand reagents.

    ______________________________________                                         ##STR238##                                                                   R.sup.1                                                                             X     m     R.sup.9        R.sup.4                                      ______________________________________                                        H     1     0                                                                                    ##STR239##                                                                                   ##STR240##                                  H     1     0                                                                                    ##STR241##                                                                                   ##STR242##                                  H     1     0                                                                                    ##STR243##                                                                                   ##STR244##                                  H     0     0                                                                                    ##STR245##    H                                            H     0     0                                                                                    ##STR246##                                                                                   ##STR247##                                  H     1     1                                                                                    ##STR248##                                                                                   ##STR249##                                  H     1     1                                                                                    ##STR250##                                                                                   ##STR251##                                  H     1     1                                                                                    ##STR252##                                                                                   ##STR253##                                  H     1     1                                                                                    ##STR254##                                                                                   ##STR255##                                  H     1     0                                                                                    ##STR256##                                                                                   ##STR257##                                  8-F   1     0                                                                                    ##STR258##                                                                                   ##STR259##                                  8-CF.sub.3                                                                          1     0                                                                                    ##STR260##                                                                                   ##STR261##                                  8-OCH.sub.3                                                                         1     0                                                                                    ##STR262##                                                                                   ##STR263##                                  8-SCH.sub.3                                                                         1     0                                                                                    ##STR264##                                                                                   ##STR265##                                  9-F   1     0                                                                                    ##STR266##                                                                                   ##STR267##                                  8-F   1     0                                                                                    ##STR268##                                                                                   ##STR269##                                  8-F   1     0                                                                                    ##STR270##                                                                                   ##STR271##                                  H     1     0                                                                                    ##STR272##    H                                            H     1     0                                                                                    ##STR273##                                                                                   ##STR274##                                  H     1     1                                                                                    ##STR275##                                                                                   ##STR276##                                  H     1     0                                                                                    ##STR277##                                                                                   ##STR278##                                  H     1     0                                                                                    ##STR279##                                                                                   ##STR280##                                  H     0     0                                                                                    ##STR281##                                                                                   ##STR282##                                  H     1     0                                                                                    ##STR283##                                                                                   ##STR284##                                  8-F   1     0                                                                                    ##STR285##                                                                                   ##STR286##                                  8-CF.sub.3                                                                          1     0                                                                                    ##STR287##                                                                                   ##STR288##                                  8-OCH.sub.3                                                                         1     0                                                                                    ##STR289##                                                                                   ##STR290##                                  8-F   1     0                                                                                    ##STR291##                                                                                   ##STR292##                                  ______________________________________                                    

EXAMPLE 65

Utilizing the procedures described in Examples 1 to 60 and generalmethods of organic synthesis described in the chemical literature andfamiliar to one skilled in the art, the following compounds of Formula 1can be prepared from the appropriately substituted starting materialsand reagents.

    __________________________________________________________________________     ##STR293##                                                                   R.sup.1                                                                           R.sup.9       A         R.sup.4                                           __________________________________________________________________________         ##STR294##                                                                                  ##STR295##                                                                              ##STR296##                                       H                                                                                  ##STR297##                                                                                  ##STR298##                                                                             CH.sub.2 CH.sub.2 OH                              H                                                                                  ##STR299##                                                                                  ##STR300##                                                                              ##STR301##                                       H                                                                                  ##STR302##                                                                                  ##STR303##                                                                              ##STR304##                                       H                                                                                  ##STR305##                                                                                  ##STR306##                                                                              ##STR307##                                       H                                                                                  ##STR308##                                                                                  ##STR309##                                                                             CH.sub.2 CH.sub.2 CH.sub.3                        H                                                                                  ##STR310##                                                                                  ##STR311##                                                                             CH.sub.3                                          H                                                                                  ##STR312##                                                                                  ##STR313##                                                                             H                                                 H                                                                                  ##STR314##                                                                                  ##STR315##                                                                             H                                                 H                                                                                  ##STR316##                                                                                  ##STR317##                                                                             H                                                 H                                                                                  ##STR318##                                                                                  ##STR319##                                                                             H                                                 H                                                                                  ##STR320##                                                                                  ##STR321##                                                                             H                                                 H                                                                                  ##STR322##                                                                                  ##STR323##                                                                             H                                                 H                                                                                  ##STR324##                                                                                  ##STR325##                                                                             H                                                 H                                                                                  ##STR326##                                                                                  ##STR327##                                                                              ##STR328##                                       H                                                                                  ##STR329##                                                                                  ##STR330##                                                                              ##STR331##                                       H                                                                                  ##STR332##                                                                                  ##STR333##                                                                              ##STR334##                                       H                                                                                  ##STR335##                                                                                  ##STR336##                                                                              ##STR337##                                       H                                                                                  ##STR338##                                                                                  ##STR339##                                                                              ##STR340##                                       H                                                                                  ##STR341##                                                                                  ##STR342##                                                                              ##STR343##                                       H                                                                                  ##STR344##                                                                                  ##STR345##                                                                              ##STR346##                                       H                                                                                  ##STR347##                                                                                  ##STR348##                                                                              ##STR349##                                       H                                                                                  ##STR350##                                                                                  ##STR351##                                                                              ##STR352##                                       H                                                                                  ##STR353##                                                                                  ##STR354##                                                                              ##STR355##                                       H                                                                                  ##STR356##                                                                                  ##STR357##                                                                              ##STR358##                                       H                                                                                  ##STR359##                                                                                  ##STR360##                                                                              ##STR361##                                       H                                                                                  ##STR362##                                                                                  ##STR363##                                                                              ##STR364##                                       H                                                                                  ##STR365##                                                                                  ##STR366##                                                                              ##STR367##                                       6-F                                                                                ##STR368##                                                                                  ##STR369##                                                                             H                                                 6-OCH.sub.3                                                                        ##STR370##                                                                                  ##STR371##                                                                             H                                                 7-Br                                                                               ##STR372##                                                                                  ##STR373##                                                                             H                                                 7-Cl                                                                               ##STR374##                                                                                  ##STR375##                                                                             H                                                 7-CH.sub.3                                                                         ##STR376##                                                                                  ##STR377##                                                                             H                                                 8-Cl                                                                               ##STR378##                                                                                  ##STR379##                                                                             H                                                 8-I                                                                                ##STR380##                                                                                  ##STR381##                                                                             H                                                 H                                                                                  ##STR382##                                                                                  ##STR383##                                                                             H                                                 H                                                                                  ##STR384##                                                                                  ##STR385##                                                                             H                                                 H                                                                                  ##STR386##                                                                                  ##STR387##                                                                             H                                                 H                                                                                  ##STR388##                                                                                  ##STR389##                                                                             H                                                 H                                                                                  ##STR390##                                                                                  ##STR391##                                                                             H                                                 H                                                                                  ##STR392##                                                                                  ##STR393##                                                                             H                                                 H                                                                                  ##STR394##                                                                                  ##STR395##                                                                             H                                                 __________________________________________________________________________

EXAMPLE 66

Utilizing the procedures described in Examples 1 to 60 and generalmethods of organic synthesis described in the chemical literature andfamiliar to one skilled in the art, the following compounds of Formula Ican be prepared from the appropriately substituted starting materialsand reagents.

    __________________________________________________________________________     ##STR396##                                                                   X   n p R.sup.9        A        R.sup.4                                       __________________________________________________________________________    --  0 3                                                                                ##STR397##                                                                                   ##STR398##                                                                            H                                             --  0 3                                                                                ##STR399##                                                                                   ##STR400##                                                                             ##STR401##                                   --  0 3                                                                                ##STR402##                                                                                   ##STR403##                                                                             ##STR404##                                   --  0 1                                                                                ##STR405##                                                                                   ##STR406##                                                                            H                                             --  0 1                                                                                ##STR407##                                                                                   ##STR408##                                                                             ##STR409##                                   --  0 1                                                                                ##STR410##                                                                                   ##STR411##                                                                             ##STR412##                                   --  0 0                                                                                ##STR413##                                                                                   ##STR414##                                                                            H                                             --  0 0                                                                                ##STR415##                                                                                   ##STR416##                                                                             ##STR417##                                   --  0 0                                                                                ##STR418##                                                                                   ##STR419##                                                                             ##STR420##                                   CO  1 1                                                                                ##STR421##                                                                                   ##STR422##                                                                             ##STR423##                                   CHOH                                                                              1 1                                                                                ##STR424##                                                                                   ##STR425##                                                                             ##STR426##                                   S   1 0                                                                                ##STR427##                                                                                   ##STR428##                                                                            H                                             S   1 0                                                                                ##STR429##                                                                                   ##STR430##                                                                            H                                             S   1 0                                                                                ##STR431##                                                                                   ##STR432##                                                                             ##STR433##                                   SO  1 0                                                                                ##STR434##                                                                                   ##STR435##                                                                            H                                             SO  1 0                                                                                ##STR436##                                                                                   ##STR437##                                                                            H                                             SO  1 0                                                                                ##STR438##                                                                                   ##STR439##                                                                             ##STR440##                                   SO  1 0                                                                                ##STR441##                                                                                   ##STR442##                                                                             ##STR443##                                   S   1 2                                                                                ##STR444##                                                                                   ##STR445##                                                                            H                                             S   1 2                                                                                ##STR446##                                                                                   ##STR447##                                                                            H                                             S   1 2                                                                                ##STR448##                                                                                   ##STR449##                                                                             ##STR450##                                   S   1 2                                                                                ##STR451##                                                                                   ##STR452##                                                                             ##STR453##                                   S   1 2                                                                                ##STR454##                                                                                   ##STR455##                                                                            H                                             S   1 2                                                                                ##STR456##                                                                                   ##STR457##                                                                            H                                             S   1 2                                                                                ##STR458##                                                                                   ##STR459##                                                                             ##STR460##                                   S   1 2                                                                                ##STR461##                                                                                   ##STR462##                                                                             ##STR463##                                   O   1 1                                                                                ##STR464##                                                                                   ##STR465##                                                                            H                                             O   1 1                                                                                ##STR466##                                                                                   ##STR467##                                                                            H                                             O   1 1                                                                                ##STR468##                                                                                   ##STR469##                                                                             ##STR470##                                   O   1 1                                                                                ##STR471##                                                                                   ##STR472##                                                                             ##STR473##                                   __________________________________________________________________________

What is claimed is:
 1. A compound having the formula: ##STR474## where Lis ##STR475## p is 0 to 3; q is 0 to 4;w is 0 or 1; R¹, R², R^(1a),R^(2a), R^(1b) and R^(2b) are independently hydrogen, halogen, C₁ -C₇alkyl, C₁ -C₃ perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, --S(O)_(m) R^(7a),cyano, nitro, R^(7b) O(CH₂)_(v) --, R^(7b) COO(CH₂)_(v) --, R^(7b)OCO(CH₂)_(v), R⁴ R⁵ N(CH₂)_(v) --, R^(7b) CON(R⁴)(CH₂)_(v) --, R⁴ R⁵NCO(CH₂)_(v) --, phenyl or substituted phenyl where the substituents arefrom 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, or hydroxy; R^(7a)and R^(7b) are independently hydrogen, C₁ -C₃ perfluoroalkyl, C₁ -C₆alkyl, substituted C₁ -C₆ alkyl, where the substituents are phenyl orsubstituted phenyl; phenyl or substituted phenyl where the phenylsubstituents are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, orhydroxy and v is 0 to 3; R^(3a) and R^(3b) are independently hydrogen,R⁹, C₁ -C₆ alkyl substituted with R⁹, phenyl substituted with R⁹, orphenoxy substituted with R⁹ with the proviso that either R^(3a) orR^(3b) must be a substituent other than hydrogen; R⁹ isR^(4b) R^(12b)NCON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12b) NCSN(R^(12a))(CH₂)_(v) --,R^(4b) R^(12c) NN(R^(12b))CSN(R^(12a))(CH₂)_(v) --, R^(4b) R^(12c)NN(R^(12b))CON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12c)NN(R^(12b))COO(CH₂)_(v) --, R^(4b) R^(12b) NCOO(CH₂)_(v) --, or R¹³OCON(R^(12a))(CH₂)_(v) --, where v is 0 to 3; R^(12a), R^(12b) andR^(12c) are independently R^(5a), OR^(5a), or COR^(5a). R^(12a) andR^(12b), or R^(12b) and R^(12c), or R^(12a) and R^(12c), or R^(12b) andR^(4b), or R^(12c) and R^(4b), or R¹³ and R^(12a) can be taken togetherto form --(CH₂)_(r) --B--(CH₂)_(s) -- where B is CHR¹, O, S(O)_(m) orNR¹⁰, m is 0, 1 or 2, r and s are independently 0 to 3 and R¹ and R¹⁰are as defined; R¹³ is:C₁ -C₃ perfluoroalkyl, C₁ -C₆ alkyl, substitutedC₁ -C₆ alkyl, where the substitutents are hydroxy, NR¹⁰ R¹¹, carboxy,phenyl or substituted phenyl; phenyl or substituted phenyl where thesubstituents on the phenyl are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁-C₆ alkoxy or hydroxy;and v is as defined above; R⁴, R^(4b), R⁵ andR^(5a) are independently hydrogen, phenyl, substituted phenyl, C₁ -C₁₀alkyl, substituted C₁ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, substituted C₃ -C₁₀alkenyl, C₃ -C₁₀ alkynyl, or substituted C₃ -C₁₀ alkynyl where thesubstituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 ofhydroxy, C₁ -C₆ alkoxy, C₃ -C₇ cycloalkyl, fluoro, R¹, R² independentlydisubstituted phenyl C₁ -C₃ alkoxy, R¹, R² independently disubstitutedphenyl, C₁ -C₂₀ -alkanoyloxy, C₁ -C₅ alkoxycarbonyl, carboxy, formyl or--NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are independently hydrogen, C₁ -C₆ alkyl,phenyl, phenyl C₁ -C₆ alkyl, C₁ -C₅ -alkoxycarbonyl or C₁ -C₅-alkanoyl-C₁ -C₆ alkyl; or R⁴ and R⁵ can be taken together to form--(CH₂)_(r) --B--(CH₂)_(s) -- where B is CHR¹, O, S(O)_(m) or N--R¹⁰, rand s are independently 1 to 3 and R¹ and R¹⁰ are as defined above; R⁶is hydrogen, C₁ -C₁₀ alkyl, phenyl or phenyl C₁ -C₁₀ alkyl; A is##STR476## where x and y are independently 0-3; R⁸ and R^(8a) areindependently hydrogen, C₁ -C₁₀ alkyl, trifluoromethyl, phenyl,substituted C₁ -C₁₀ alkyl where the substituents are from 1 to 3 ofimidazolyl, indolyl, hydroxy, fluoro, S(O)_(m) R^(7a), C₁ -C₆ alkoxy, C₃-C₇ cycloalkyl, R¹, R² independently disubstituted phenyl C₁ -C₃ alkoxy,R¹, R² independently disubstituted phenyl, C₁ -C₅ -alkanoyloxy, C₁ -C₅alkoxycarbonyl, carboxy, formyl, or --NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are asdefined above; or R⁸ and R^(8a) can be taken together to form--(CH₂)_(t) -- where t is 2 to 6; and R⁸ and R^(8a) can independently bejoined to one or both of R⁴ and R⁵ to form alkylene bridges between theterminal nitrogen and the alkyl portion of the A group wherein thebridge contains from 1 to 5 carbon atoms;and pharmaceutically acceptablesalts thereof.
 2. A compound of claim 1 wherein:p is 0 to 3; q is 0 to2; w is 0 or 1; R¹, R², R^(1a), R^(2a), R^(1b) and R^(2b) areindependently hydrogen, halogen, C₁ -C₇ alkyl, C₁ -C₃ perfluoroalkyl,--S(O)_(m) R^(7a), R^(7b) O(CH₂)_(v) --, R^(7b) COO(CH₂)_(v) --, R^(7b)OCO(CH₂)_(v) --, phenyl or substituted phenyl where the substituents arefrom 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy or hydroxy; R^(7a)and R^(7b) are independently hydrogen, C₁ -C₃ perfluoroalkyl, C₁ -C₆alkyl, substituted C₁ -C₆ alkyl, where the substituents are phenyl;phenyl and v is 0 to 2; R^(3a) and R^(3b) are independently hydrogen,R⁹, C₁ -C₆ alkyl substituted with R⁹, phenyl substituted with R⁹, orphenoxy substituted with R⁹ with the proviso that either R^(3a) orR^(3b) must be a substituent other than hydrogen; R⁹ isR^(4b) R^(12b)NCON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12b) NCSN(R^(12a))(CH₂)_(v) --,R^(4b) R^(12c) NN(R^(12b))CON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12c)NN(R^(12b))COO(CH₂)_(v) --, R^(4b) R^(12b) NCOO(CH₂)_(v) -- or R¹³OCON(R^(12a))(CH₂)_(v) --, where v is 0 to 3; R^(12a), R^(12b) andR^(12c) are independently R^(5a), OR^(5a), or COR^(5a). R^(12a) andR^(12b), or R^(12b) and R^(12c), or R^(12a) and R^(12c), or R^(12b) andR^(4b), or R^(12c) and R^(4b), or R¹³ and R^(12a) can be taken togetherto form --(CH₂)_(r) --B--(CH₂)_(s) -- where B is CHR¹, O, S(O)_(m) orNR¹⁰, m is 0, 1 or 2, r and s are independently 0 to 3, R¹ is as definedabove and R¹⁰ is hydrogen, C₁ -C₆ alkyl, phenyl C₁ -C₆ alkyl or C₁ -C₅alkanoyl-C₁ -C₆ alkyl; R¹³ isC₁ -C₃ perfluoroalkyl, C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, where the substituents are hydroxy, NR¹⁰ R¹¹,carboxy, phenyl or substituted phenyl; phenyl or substituted phenylwhere the substituents on the phenyl are from 1 to 3 of halogen, C₁ -C₆alkyl, C₁ -C₆ alkoxy or hydroxy;where v is as defined above; R⁴, R^(4b),R⁵ and R^(5a) are independently hydrogen, phenyl, substituted phenyl, C₁-C₁₀ alkyl, substituted C₁ -C₁₀ alkyl, where the substituents on thealkyl or phenyl are from 1 to 5 of hydroxy, C₁ -C₆ alkoxy, C₃ -C₇cycloalkyl, fluoro, R¹, R² independently disubstituted phenyl C₁ -C₃alkoxy, R¹, R² independently disubstituted phenyl, C₁ -C₂₀ -alkanoyloxy,C₁ -C₅ alkoxycarbonyl, carboxy or formyl; R⁴ and R⁵ can be takentogether to form --(CH₂)_(r) --B--(CH₂)_(s) -- where B is CHR¹, O,S(O)_(m) or N--R¹⁰, r and s are independently 1 to 3 and R¹ and R¹⁰ areas defined above; R⁶ is hydrogen, C₁ -C₁₀ alkyl or phenyl C₁ -C₁₀ alkyl;A is ##STR477## where x and y are independently 0-2; R⁸ and R^(8a) areindependently hydrogen, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl wherethe substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy,fluoro, S(O)_(m) R^(7a), C₁ -C₆ alkoxy, R¹, R² independentlydisubstituted phenyl, C₁ -C₅ -alkanoyloxy, C₁ -C₅ alkoxycarbonyl,carboxy, formyl, --NR¹⁰ R¹¹ where R¹⁰ and R¹¹ are independentlyhydrogen, C₁ -C₆ alkyl or C₁ -C₅ alkanoyl-C₁ -C₆ alkyl; or R⁸ and R^(8a)can be taken together to form --(CH₂)_(t) -- where t is 2 to 4; and R⁸and R^(8a) can independently be joined to one or both of R⁴ and R⁵ toform alkylene bridges between the terminal nitrogen and the alkylportion of the A group wherein the bridge contains from 1 to 5 carbonatoms;and pharmaceutically acceptable salts thereof.
 3. A compound ofclaim 2 wherein:p is 0 to 2; q is 0 to 2; w is 0 or 1; R¹, R², R^(1a),R^(2a), R^(1b), and R^(2b) are independently hydrogen, halogen, C₁ -C₇alkyl, C₁ -C₃ perfluoroalkyl, --S(O)_(m) R^(7a), R^(7b) O(CH₂)_(v) --,R^(7b) COO(CH₂)_(v) --, R^(7b) OCO(CH₂)_(v) --, phenyl or substitutedphenyl where the substituents are from 1 to 3 of halogen, C₁ -C₆ alkyl,C₁ -C₆ alkoxy, or hydroxy; R^(7a) and R^(7b) are independently hydrogen,C₁ -C₆ alkyl or substituted C₁ -C₆ alkyl where the substituents arephenyl and v is 0 to 2; R^(3a) and R^(3b) are independently hydrogen,R⁹, C₁ -C₆ alkyl substituted with R⁹, phenyl substituted with R⁹ orphenoxy substituted with R⁹ with the proviso that either R^(3a) orR^(3b) must be a substituent other than hydrogen; R⁹ is R^(4b) R^(12b)NCON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12b) NCSN(R^(12a))(CH₂)_(v) --,R^(4b) R^(12c) NN(R^(12b))CON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12c)NN(R^(12b))COO(CH₂)_(v) --, R^(4b) R^(12b) NCOO(CH₂)_(v) -- or R¹³OCON(R^(12a))(CH₂)_(v) --, where v is 0 to 2; R^(12a), R^(12b) andR^(12c) are independently R^(5a), OR^(5a), or COR^(5a). R^(12a) andR^(12b), or R^(12b) and R^(12c), or R^(12a) and R^(12c), or R^(12b) andR^(4b), or R^(12c) and R^(4b), or R¹³ and R^(12a) can be taken togetherto form --(CH₂)_(r) --B--(CH₂)_(s) -- where B is CHR¹, O, S(O)_(m) orNR¹⁰, m is 0, 1 or 2, r and s are independently 0 to 2, R¹ is as definedabove and R¹⁰ is hydrogen, C₁ -C₆ alkyl or C₁ -C₅ alkanoyl-C₁ -C₆ alkyl;R¹³ isC₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, where the substituents arephenyl or substituted phenyl; phenyl or substituted phenyl where thesubstituents on the phenyl are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁-C₆ alkoxy or hydroxy; R⁴, R^(4b), R⁵ and R^(5a) are independentlyhydrogen, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl, where thesubstituents on the alkyl are from 1 to 5 of hydroxy, C₁ -C₆ alkoxy,fluoro, R¹, R² independently disubstituted phenyl, C₁ -C₂₀ -alkanoyloxy,C₁ -C₅ alkoxycarbonyl or carboxy; R⁶ is hydrogen or C₁ -C₁₀ alkyl; A is##STR478## where x and y are independently 0-2; R⁸ and R^(8a) areindependently hydrogen, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl wherethe substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy,fluoro, S(O)_(m) R^(7a), C₁ -C₆ alkoxy, R¹, R² independentlydisubstituted phenyl, C₁ -C₅ -alkanoyloxy, C₁ -C₅ alkoxycarbonyl,carboxy; or R⁸ and R^(8a) can be taken together to form --(CH₂)_(t) --where t is 2; or R⁸ and R^(8a) can independently be joined to one orboth of R⁴ and R⁵ to form alkylene bridges between the terminal nitrogenand the alkyl portion of the A group wherein the bridge contains from 1to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
 4. Acompound of claim 3 wherein:p is 0 to 2; q is 1; w is 1; R¹, R², R^(1a),R^(2a), R^(1b) and R^(2b) are independently hydrogen, halogen, C₁ -C₇alkyl, C₁ -C₃ perfluoroalkyl, --S(O)_(m) R^(7a), R^(7b) O(CH₂)_(v) --,R^(7b) COO(CH₂)_(v) --, phenyl or substituted phenyl where thesubstituents are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy orhydroxy; R^(7a) and R^(7b) are independently hydrogen, C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, where the substituents are phenyl and v is 0or 1; R^(3a) and R^(3b) are independently hydrogen, R⁹, or C₁ -C₆ alkylsubstituted with R⁹ with the proviso that either R^(3a) or R^(3b) mustbe a substituent other than hydrogen; R⁹ isR^(4b) R^(12b)NCON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12c)NN(R^(12b))CON(R^(12a))(CH₂)_(v) --, R^(4b) R^(12c)NN(R^(12b))COO(CH₂)_(v) --, R^(4b) R^(12b) NCOO(CH₂)_(v) -- or R¹³OCON(R^(12a))(CH₂)_(v) --, where v is 0 or 1; R^(12a), R^(12b) andR^(12c) are independently R^(5a), OR^(5a), or COR^(5a). R^(12a) andR^(12b), or R^(12b) and R^(12c), or R^(12a) and R^(12c), or R^(12b) andR^(4b), or R^(12c) and R^(4b), or R¹³ and R^(12a) can be taken togetherto form --(CH₂)_(r) --B--(CH₂)_(s) -- where B is CHR¹, O, S(O)_(m) orNR¹⁰, m is 0, 1 or 2, r and s are independently 0 to 2, R¹ is as definedabove and R¹⁰ is hydrogen, C₁ -C₆ alkyl or C₁ -C₅ alkanoyl-C₁ -C₆ alkyl;R¹³ isC₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, where the substituents arephenyl or substituted phenyl; phenyl or substituted phenyl where thesubstituents on the phenyl are from 1 to 3 of halogen, C₁ -C₆ alkyl, C₁-C₆ alkoxy or hydroxy; R⁴, R^(4b), R⁵ and R^(5a) are independentlyhydrogen, C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl, where thesubstituents on the alkyl are from 1 to 3 of hydroxy, C₁ -C₃ alkoxy,fluoro, R¹, R² independently disubstituted phenyl, C₁ -C₂₀ alkanoyloxy,C₁ -C₅ alkoxycarbonyl or carboxy; R⁶ is hydrogen; A is ##STR479## wherex and y are independently 0-1; R⁸ and R^(8a) are independently hydrogen,C₁ -C₁₀ alkyl, substituted C₁ -C₁₀ alkyl where the substituents are from1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)_(m) R^(7a), C₁ -C₆alkoxy, R¹, R² independently disubstituted phenyl, C₁ -C₅ -alkanoyloxy,C₁ -C₅ alkoxycarbonyl, carboxy; or R⁸ and R^(8a) can be taken togetherto form --(CH₂)_(t) -- where t is 2; and R⁸ and R^(8a) can independentlybe joined to one or both of R⁴ and R⁵ to form alkylene bridges betweenthe terminal nitrogen and the alkyl portion of the A group wherein thebridge contains from 1 to 5 carbon atoms;and pharmaceutically acceptablesalts thereof.
 5. A stereospecific compound of claim 1 having thefollowing structural formula: ##STR480## where R¹, R², p, q, L, w,R^(1a), R^(2a), R^(3a), R⁴, R⁵, R⁶ and A are as defined in claim
 1. 6.The compound of claim 4 wherein v is
 1. 7. A compound which is selectedfrom the group consisting of:2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1-2'- (methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoro-methyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide; -2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(aminocarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!-amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!-methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(ethylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!propanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!methyl!1,1'-bi-phenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!-methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!-methyl!1,1'-biphenyl!-4-yl!methyl!-7-fluoro-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!-methyl!1,1'-biphenyl!-4-yl!methyl!-7-methoxy-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!-methyl!1,1'-biphenyl!-4-yl!methyl!-7-methylthio-2-oxo-1H-benzazepin-3(R)-yl!butanamide;3- 2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(hydroxyethyl)amino!carbonyl!amino!-methyl!1,1'-biphenyl!-4-yl!methyl!-7-trifluoromethyl-2-oxo-1H-benzazepin-3(R)-yl!butanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'- 2-(methylamino)carbonyl!amino!prop-2-yl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'- 1-(methylamino)carbonyl!amino!ethyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!-methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methoxycarbonyl)amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;3-Amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(R)-Hydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!-methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide; 3-2(S),3-Dihydroxypropyl!amino-3-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!oxy!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!butanamide;or apharmaceutically accepteble salt thereof.
 8. A compound whichis:2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide;or apharmaceutically accepteble salt thereof.
 9. The compound of claim 8which is:2-Amino-2-methyl- N- 2,3,4,5-tetrahydro-1- 2'-(methylamino)carbonyl!amino!methyl!1,1'-biphenyl!-4-yl!methyl!-2-oxo-1H-benzazepin-3(R)-yl!propanamide,hydrochloride.
 10. A process for the preparation of a compound of claim1 which comprises reacting a compound having a formula: ##STR481## whereR¹, R², R⁶, and p are as defined in claim 1 with a compound having theformula: ##STR482## where R⁵ and A are as defined in claim 1 and G is aprotecting group; which step is either followed by or preceded by thetreatment of the compound with ##STR483## where R^(1a), R^(2a), R^(3a),L, w and q are as defined in claim 1 and Y is a leaving group, followedby the replacement of the protecting group G with R⁴.
 11. The process ofclaim 10 where compound III is first reacted with compound IV followedby reaction with compound VI.
 12. A process for the preparation of acompound of claim 1 which comprises reacting a compound having aformula: ##STR484## where R¹, R², R⁵, R⁶, A, and p are as defined inclaim 1 and G is a protecting group, with a compound having the formula:##STR485## where R^(1a), R^(2a), R^(3a), L, w and q are as defined inclaim 1 and Y is a leaving group, followed by replacement of theprotecting group G with R⁴.
 13. The process of claim 12 where theprotecting group G is t-butoxycarbonyl or benzyloxycarbonyl and Y ischlorine, bromine, iodine, O-methanesulfonyl or O-(p-toluenesulfonyl).14. A method for increasing levels of endogenous growth hormone in ahuman or an animal which comprises administering to such human or animalan effective amount of a compound of claim
 1. 15. A composition usefulfor increasing the endogenous production or release of growth hormone ina human or an animal which comprises an inert carrier and an effectiveamount of a compound of claim
 1. 16. A composition useful for increasingthe endogenous productionelease of growth hormone in a human or ananimal which comprises an inert carrier and an effective amount of acompound of claim 1 used in combination with other growth hormonesecretagogues such as GHRP-6, GHRP-1, GHRP-2, B-HT 920 or growth hormonereleasing factor (GRF) or one of its analogs, or IGF-1 or IGF-2.
 17. Amethod for the treatment of obesity which comprises administering to anobese patient a compound of claim 1 in combination with an α₂ adrenergicagonist or β₃ adrenergic agonist.
 18. A composition for the treatment ofobesity which comprises an inert carrier and a compound of claim 1 incombination with an α₂ adrenergic agonist or β₃ adrenergic agonist. 19.A method for the treatment of osteoporosis which comprises administeringto a patient with osteoporosis a compound of claim 1 in combination withparathyroid hormone or a bisphosphonate.
 20. A composition for thetreatment of osteoporosis which comprises an inert carrier and acompound of claim 1 in combination with parathyroid hormone or abisphosphonate.
 21. A method for the treatment of the catabolic effectsof nitrogen wasting which comprises administering to such patient acompound of claim 1 in combination with insulin-like growth factor I(IGF-I).
 22. A composition for the treatment of the catabolic effects ofnitrogen wasting which comprises an inert carrier and a compound ofclaim 1 in combination with insulin-like growth factor I (IGF-I).